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The Golgin Coiled-Coil of the

Sean Munro

MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom Correspondence: [email protected]

A number of long coiled-coil proteins are present on the Golgi. Often referred to as “golgins,” they are well conserved in evolution and at least five are likely to have been present in the last common ancestor of all eukaryotes. Individual golgins are found in different parts of the Golgi stack, and they are typically anchored to the membrane at their carboxyl termini by a transmembrane domain or by binding a small GTPase. They appear to have roles in mem- brane traffic and Golgi structure, but their precise function is in most cases unclear. Many have binding sites for Rab family GTPases along their length, and this has led to the sugges- tion that the golgins act collectively to form a tentacular matrix that surrounds the Golgi to capture Rab-coated membranes in the vicinity of the stack. Such a collective role might explain the lack of cell lethality seen following loss of some of the in human familial conditions or mouse models.

oiled-coils are widely occurring of the protein is predicted to form a coiled-coil, Cstructural motifs in which two or more and that their carboxyl termini mediate attach- a-helices wind around each other to form an ment to Golgi membranes. They are generally extended rod-like structure. Proteins contain- ubiquitously expressed and well conserved in ing such structures are found in many parts of evolution, but their coiled-coil regions are rela- the cell, and play diverse roles including organ- tively poorly conserved suggesting that much of izing centrosomes, chromatin, and synapses, or their length serves as spacer. Given that 500 res- serving as molecular motors. As such there idues of coiled-coil is 75 nm in length then may seem little reason to consider them col- the proteins could extend for 100–400 nm. lectively beyond an interest in the structural Some of the proteins have regions which appear and biophysical properties of the coiled-coil likely to be unstructured and hence could serve itself. However, the Golgi is unique amongst as extensions or hinges to increase the proteins’ the cellular compartments in that several differ- reach and flexibility (Oas and Endow 1994; ent large coiled-coil proteins are present on its Yamakawa et al. 1996). These shared features cytoplasmic surface (Gillingham and Munro suggest that the proteins serve related functions 2003; Lupashin and Sztul 2005; Short et al. on the Golgi. The term “golgin” is often applied 2005; Ramirez and Lowe 2009). A number of to these proteins having been coined in early these share a similar organization in that most studies when several were found as human

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autoantigens (Fritzler et al. 1993), but the term how their properties might reflect a shared lacks a clear definition. Toprovide a focus to this function in Golgi organization and traffic. article, I will concentrate on “golgins” as defined by being a protein that is found primarily, if not exclusively, on the Golgi and is predicted GOLGINS AT THE CIS-GOLGI: GM130, to form a homodimeric parallel coiled-coil GMAP-210, AND GOLGIN-160 over most of its length. Proteins with shorter regions of coiled-coil are more likely to have GM130 and its Relatives roles distinct to the golgins, especially if further Identified as a Golgi autoantigen, GM130 is a domains are present. ubiquitously expressed protein of the cis-Golgi Golgin coiled-coil proteins are found on (Fritzler et al. 1993; Nakamura et al. 1995). the cis-face of the Golgi, around the rims of The carboxyl terminus of the rat protein has the stack and on the trans-face of the Golgi been shown to bind the lipid-anchored PDZ (Fig. 1). The human golgins are summarized domain protein GRASP65, and this region of in Table 1, along with their orthologs in model the protein is required for Golgi localization organisms and the rather confusing names (Barr et al. 1997; Barr et al. 1998). The protein inflicted by the Human is conserved in metazoans and fungi, and a Committee. I discuss what is known about the diminutive yeast ortholog, Bug1, binds to the individual proteins from each of the parts of yeast ortholog of GRASP65 (Behnia et al. the Golgi, and mention briefly the Golgi 2007). However the protein does not appear coiled-coil proteinsthat are probably not golgins. to have orthologs outside of opisthikonts, in I then discuss how the golgins are regulated and contrast to GRASP65 which is conserved in

cis Golgi GM130 GMAP-210 Golgin-160

Golgi rims Giantin

Golgin-84 CASP

trans Golgi Golgin-245 GCC185 Golgin-97 GCC88 TMF1

Predicted coiled-coil TMD 500 aa GRIP GRAB ALPS

Figure 1. The golgin coiled-coil proteins of humans. Schematic representations of known human golgins. Regions predicted to form coiled-coils are shown in gray, and known domains involved in protein function or subcellular targeting are indicated.

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The Golgin Coiled-Coil Proteins

Table 1. The canonical golgins of the human Golgi and their orthologs. Protein Alternative Human gene D. melanogaster C. elegans S. cerevisiae A. thaliana names symbol GM130 golgin-95 GOLGA2 CG11061 F33G12.5 BUG1 GMAP-210 Trip230 TRIP11 CG7821 Y111B2A.4 RUD3 At3g6157 CEV14 At2g46180 golgin-160 Mea-2 GOLGA3 IIGP165 GCP170 golgin-84 RFG5 GOLGA5 CG17785 T24B1.1 At1g18190 At2g19950 CASP CUX1 (alt) Y54F10AM.4c COY1 At3g18480 (ceh-44) giantin macrogolgin GOLGB1 CG6450 GCP372 (lva) golgin-97 GOLGA1 CG4840 IMH1 At5g66030 (cbs) golgin-245 p230 GOLGA4 CG3493 F59A2.2/6 tGolgin-1 GCC88 GCC1 CG10703 C15C7.2.1 (klp-8) GCC185 GCC2 CG3532 T05G5.9 TMF ARA160 TMF1 CG4557 F39H12.1 SGM1 At1g79830

protozoa, and has been reported to have roles in temperature sensitive, it shows no defects in Golgi structure and the traffic of specific cargo Golgi structure or protein transport at the beyond binding GM130 (D’Angelo et al. 2009; permissive temperature (Vasile et al. 2003). Xiang and Wang 2010). GM130 is also the Golgi binding site of a protein GM130 has been shown to interact via its kinase linked to directed cell migration, and is amino terminus with p115, a cytosolic protein also suggested to have roles in SNARE assembly that is comprised of armadillo repeats followed and regulation of centrosomes (reviewed in by a region of coiled-coil, and which has been Nakamura 2010). shown to be involved in tethering ER-derived In addition to GM130, the transport vesicles to the Golgi in mammals contains a family of over 30 genes that are and yeast (Sapperstein et al. 1995; Nakamura related to GM130 and are referred to as GOL- et al. 1997; Cao et al. 1998; Satoh and Warren GA6A-J, GOLGA6AL1-10, and GOLGA8A-J 2008; An et al. 2009; Striegl et al. 2010). (Jiang et al. 2008). Most are present in the re- GM130 is also an effector for the small GTPases peats of an element that derived from GOLGA2, Rab1, Rab30, and Rab33b (Moyer et al. 2001; the gene encoding GM130 on 9, Valsdottir et al. 2001; Weide et al. 2001; Sinka but has duplicated on the long arm of chromo- et al. 2008). However, it seems unlikely that some 15. These repeats appear to have been GM130 is essential for membrane traffic as a generated by genome rearrangements during mutant Chinese hamster cell line has been iden- primate evolution as similar repeats are found tified that lacks detectable GM130 and although in the genome of the macaque, an old-world

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monkey, whereas nonprimate vertebrates such of GMAP-210 causes IFT20 to be displaced as mice only have the GOLGA2 gene (Zody from the Golgi (Follit et al. 2008). et al. 2006). These genes are unlikely to all be A null mutant in mouse GMAP-210 results pseudogenes as they are predicted to encode in impaired skeletal development, and loss-of- proteins and are well represented in EST function mutations in the human gene have databases. They are generally internally deleted been found to underlie some cases of familial versions of GM130 and one, golgin-67 (GOL- skeletal dysplasia (Smits et al. 2010). In the GA8A), has been shown to be widely expressed mutant mice there is a defect in secretion of and present on the Golgi (Eystathioy et al. 2000; extracellular matrix by chondrocytes, and Golgi Jakymiw et al. 2000). Their significance is structure appears perturbed, but effects on cilia unclear, and may be difficult to address, but at are disputed (Follit et al. 2008; Smits et al. the very least, they are relevant to the study of 2010). Genetic studies in Drosophila and yeast GM130 function in primate cell lines. also show that the protein is not essential for bulk secretion, but the yeast ortholog shows several genetic interactions with known compo- GMAP-210 nents of machinery for traffic through the early GMAP-210 was reported as one of several hits Golgi (Kim et al. 1999; VanRheenen et al. 1999; from a yeast-two hybrid screen with the thyroid Gillingham et al. 2004; Friggi-Grelin et al. hormone receptor and so the human gene is 2006). named TRIP11 for thyroid receptor interacting protein 11 (Lee et al. 1995). It has also been reported to bind , retinoblastoma Golgin-160 protein, and centrosomes (Infante et al. 1999). However, the protein is located to the cis-face First identified in humans as an autoantigen, of the Golgi (Rios et al. 1994), and in mammals, golgin-160 is located to the cis-Golgi, and yeast, and plants, the carboxy-terminal region orthologs are present only in deuterosomes is sufficient to confer a Golgi localization (Fritzler et al. 1993). The amino-terminal 400 (Gillingham et al. 2004; Latijnhouwers et al. residues appear to be a conserved domain of 2007). The carboxy-terminal region contains a unknown function, whilst the remaining 1100 well conserved GRAB domain which is related residues are predicted to form a coiled-coil. Its to the GRIP domain described below. The mouse ortholog Mea2 was found as a gene GRAB domain binds the small G protein Arf1, expressed at high levels in testes with uniform although in mammals binding of the GRAB low expression elsewhere (Su et al. 1992). A domain to Golgi membranes appears to be sta- mouse mutant has been identified in which bilized by an adjacent amphipathic helix (Drin Mea2 is inadvertently disrupted by a transgene et al. 2008). (Matsukuma et al. 1999). This results in loss The protein is predicted to be coiled-coil of the first 488 residues and variable expression, over most of its length, but the amino-terminal with the lowest expression levels (about 5% of 38 residues of the human protein have been normal) correlating with defects in spermato- shown to form an ALPS (amphipathic lipid- genesis (Banu et al. 2002). packing sensor) motif (Drin et al. 2008). This The function of Golgin-160, and how it is motif binds preferentially to highly curved recruited to the Golgi is unclear. It has been membranes leading to the suggestion that the reported to interact with three cytoplasmic pro- amino terminus could tether transport vesicles teins of unknown function, GCP16 (GOLGA7), to the Golgi, although this is unlikely to be the ACBD3 (GCP60), and GOPC (PIST) (Ohta only interaction made by the protein as the et al. 2003; Hicks and Machamer 2005; Sbodio ALPS motif is not well conserved outside of ver- et al. 2006). The ACBD3 interaction is induced tebrates. GMAP-210 has also been reported to by apoptosis, but the GOPC interaction may be bind IFT20, a component of cilia, and removal relevant to normal function as mice mutants

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The Golgin Coiled-Coil Proteins

lacking GOPC also show defects in spermato- Human golgin-84 was found as a probable genesis (Yao et al. 2002). false-positive in a yeast two-hybrid screen and is well conserved in evolution with orthologs in plants, but not fungi (Bascom et al. 1999). The third member of the family, CASP, was GOLGINS ON THE RIM OF THE GOLGI found by searching for proteins with a TMD STACK: GIANTIN, GOLGIN-84, AND CASP related to those of giantin and golgin-84 (Gil- Three golgins have a transmembrane domain at lingham et al. 2002). In metazoans it is pro- their carboxyl terminus, and these transmem- duced by from a gene that brane domains are related as they share con- also encodes a transcription factor called cut- served polar residues (Gillingham et al. 2002). like 1 (CDP/CUX1), but this seems to reflect In addition, all three proteins appear to be local- a rearrangement in metazoan evolution because ized to the rim of the Golgi stack and in COPI CASP is well conserved outside of metazoans vesicles, although the latter location would be being present in fungi, plants, and Trypano- obligatory for any integral somes where it is present as a single contiguous resident in the Golgi if, as is widely believed, gene. The precise functions of CASP and gol- COPI vesicles mediate the retrograde traffic of gin-84 are unclear, although they coprecipitate Golgi residents as cisternae mature (Martinez- from mammalian cells and it has been suggested Mena´rguez et al. 2001; Oka et al. 2004). For at that this interaction could mediate tethering of least CASP and golgin-84, the carboxy-terminal COPI vesicles to the Golgi (Gillingham et al. region including the transmembrane domain 2002; Malsam et al. 2005). However, both pro- is sufficient to confer a Golgi localization on a teins are not always conserved in the same spe- reporter (Bascom et al. 1999; Gillingham et al. cies with fungi having CASP but not golgin-84 2002; Renna et al. 2005). and Drosophila having golgin-84 but not Giantin was found as the target of a mono- CASP. Removal by RNAi of golgin-84 in cul- clonal raised against Golgi mem- tured cells results in Golgi fragmentation, but branes, and also identified as a human forward transport continues (Diao et al. 2003; autoantigen (Linstedt and Hauri 1993; Seelig Sohda et al. 2010). In addition, the yeast ortho- et al. 1994). It appears to be present only in ver- log of CASP, Coy1, shows genetic interactions tebrates, although Drosophila have a similarly with components of Golgi membrane traffic large Golgi coiled-coil protein called Lava (Gillingham et al. 2002). lamp (Sisson et al. 2000). This protein lacks a TMD but shares some sequence features with giantin and so may be a distant ortholog in GOLGINS AT THE TRANS-GOLGI: THE GRIP insects. Giantin is predicted to be coiled-coil DOMAIN GOLGINS AND TMF over most of its length, and so if fully extended GRIP Domain Golgins would project at least 450 nm from the mem- brane. It has been found to interact with p115 In mammals there are four golgins that share a and thus suggested to play a role in vesicle teth- domain of about 80 residues at their carboxyl ering in conjunction with GM130, although the terminus called the GRIP domain (golgin-97, details of this are disputed (So¨nnichsen et al. RanBP2a, Imh1p, and p230/golgin-245, (Barr 1998; Lesa et al. 2000; Linstedt et al. 2000). 1999; Kjer-Nielsen et al. 1999; Munro and Like golgin-160, it has been reported to bind Nichols 1999)). These four proteins are also ACBD3/GCP60, a protein of unknown func- conserved in most invertebrates, whilst a single tion (Sohda et al. 2001). The role of giantin itself GRIP domain protein is present in the genome may be redundant with other golgins as knock- of many nonmetazoan organisms including down of the protein by antibody injection has fungi, plants, and protozoa. Golgin-97 and gol- no detectable effect on Golgi structure or traffic gin-245 were identified as human autoantigens, (Puthenveedu and Linstedt 2001). and then GCC88 and GCC185 were identified

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by genome searches for further GRIP domain- traffic from endosomes to Golgi (Tsukada containing proteins (Erlich et al. 1996; Griffith et al. 1999). et al. 1997; Luke et al. 2003). All the GRIP domain proteins appear to be TMF on the trans-side of the Golgi and the GRIP Originally identified as a hit in screens for bind- domain has been shown to mediate Golgi tar- ing to a TATA element (hence TMF for TATA geting in mammals, yeast, plants, and Trypano- element modulatory factor) or to the androgen somes (McConville et al. 2002; Latijnhouwers receptor, TMF was subsequently observed to be et al. 2005). In all of these species the Golgi tar- on the Golgi (Garcia et al. 1992; Hsiao and geting of the GRIP domain has been found to Chang 1999; Mori and Kato 2002). It is well depend on binding to a small G protein of the conserved in evolution with a single ortholog trans-Golgi called Arf-like 1 (Arl1) (VanValken- in all metazoans so far examined as well as in burgh et al. 2001; Lu and Hong 2003; Panic et al. fungi, plants and Dictyostelium (Fridmann-Sir- 2003b; Setty et al. 2003; Stefano et al. 2006). kis et al. 2004; Latijnhouwers et al. 2007). Dele- Structural studies of a complex between tion of the S. cerevisiae ortholog Sgm1 results in Arl1-GTP and the GRIP domain of human no clear Golgi or trafficking defect, but the pro- golgin-245 revealed that the GRIP domain is tein binds to Ypt6, the yeast ortholog of Rab6, formed of three short a helixes, and dimerizes via its carboxyl terminus, and requires Ypt6 to allow simultaneous binding to two Arl1-GTP for its Golgi localization (Siniossoglou and Pel- molecules (Panic et al. 2003a; Wu et al. 2004). ham 2001). The mammalian protein also binds There has been some debate as to whether or to Rab6 through its carboxyl terminus and this not mammalian Arl1 can bind the GRIP part of the protein is sufficient for Golgi target- domain of GCC185, and whether an adjacent ing. Rab6 is found on the trans-side of the interaction with Rab6 is important for Golgi Golgi, but TMF has not been localized by targeting, but as of yet no alternative interaction immunoelectron microscopy, and at the light partner for the GCC185 GRIP domain has been level appears more similar to giantin at the identified (Panic et al. 2003a; Burguete et al. Golgi rims than to TGN markers (Fridmann- 2008; Houghton et al. 2009). In some cases, Sirkis et al. 2004; Yamane et al. 2007). the GRIP domain is followed by a short amphi- When TMF is knocked down by RNAi in pathic helix that may interact with the lipid mammalian cells, the Golgi becomes frag- bilayer to stabilize membrane association (Panic mented and there is a defect in retrograde trans- et al. 2003a). port from endosomes to the Golgi (Fridmann- The role of the mammalian GRIP domain Sirkis et al. 2004; Yamane et al. 2007). However, proteins has been investigated by RNAi in cul- knockout mice lacking TMF develop normally tured cells. Knockdown of individual proteins and the females are fertile whilst the male can result in fragmentation of the Golgi, and mice show defects in sperm formation, but no defects in the retrograde traffic of some cargo defects in expression of an androgen receptor proteins from endosomes to the TGN (Lu et al. regulated gene (Lerer-Goldshtein et al. 2010). 2004; Yoshino et al. 2005; Reddy et al. 2006; TMF is expressed ubiquitously, but at higher Derby et al. 2007; Lieu et al. 2007; Hayes et al. levels in the testes, and so may contribute to 2009). It has also been suggested that at least acrosome formation, as this is defective in the some GRIP domain proteins are associated mutant mice. with carriers leaving the Golgi for the plasma membrane and thus they could help in the NONGOLGIN GOLGI COILED-COIL exit of specific cargo proteins from the TGN PROTEINS (Lieu et al. 2008). The single GRIP domain pro- tein in yeast, Imh1, is not essential for secretion There are several other proteins on the Golgi or viability but shows strong genetic interac- which contain coiled-coil domains but whose tion with other proteins involved in retrograde properties suggest that their roles are likely to

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The Golgin Coiled-Coil Proteins

be distinct to those of the golgins, of which the et al. 2003). Scyl1 has been proposed to have a most obvious are the SNARE proteins that form variety of roles including an association with four helical bundles to drive membrane fusion. COPI vesicles (Burman et al. 2010), and its Others include p115 which acts in vesicle tether- relative Scyl3/CVAK104 is associated with ing and whose carboxy-terminal 300 residues clathrin-coated vesicles (Conner and Schmid are predicted to be coiled-coil (Barroso et al. 2005; Borner et al. 2007). However the physio- 1995; Sapperstein et al. 1995; Sohda et al. logical significance of the interaction between 2005). However, most of the length of p115 enc- Scyl1 and SCYL1BP1 is uncertain as mice odes a large amino-terminal domain that is lacking Scyl1 show a very different phenotype composed of armadillo repeats which are unre- (neurodegeneration and muscle wasting) to lated to the golgins (An et al. 2009; Striegl et al. that seen in patients with loss-of-function 2010). The dynein adaptor Bicaudal-1/2is mutations in SCYL1BP1 (Schmidt et al. 2007). coiled-coil over most of its length and binds The function of SCYLBP1 itself is also unclear Rab6 at the carboxyl terminus, but is also found as fibroblasts from patients lacking the protein in other parts of the cell (Matanis et al. 2002; have no obvious defect in Golgi morphology Short et al. 2002; Kardon and Vale 2009). There (Hennies et al. 2008). are also some Golgi proteins of unknown func- tion that have short regions of coiled such as ERC1/RAB6IP2 SCOCO and the Rab2 effector golgin-45 (Short et al. 2001; Van Valkenburgh et al. 2001). In Originally identified in ayeast two hybrid screen addition, the neuroendocrine coiled-coil pro- with Rab6, ERC1/RAB6IP2 is predicted to be teins NECC1/2 were reported to be predomi- mostly composed of a stretch of over 800 resi- nantly near the Golgi, but this has not been dues of coiled-coil (Monier et al. 2002). It exists seen in subsequent studies (Cruz-Garcia et al. in multiple alternatively spliced versions all of 2007; Vidal et al. 2009). Two further coiled-coil which have one of two different carboxyl ter- proteins, SCYLBP1 and ERC1, have been pro- mini depending on the inclusion of an optional posed to be golgins, but either lack extensive exon (Nakata et al. 2002; Wang et al. 2002; Hida coiled-coils or are not exclusively on the Golgi. and Ohtsuka 2010). Inclusion of the exon Nonetheless, they are worth more detailed con- results in the carboxyl terminus IWA, and sideration as they are of considerable current such forms are found exclusively in the brain, interest. whilst exclusion results in a carboxy-terminal extension that is ubiquitously present outside of the brain. This carboxy-terminal extension SCYL1BP1 resembles the Rab-binding domain from the Null mutations in the gene encoding SCYL1BP1 FIP family of Rab11 binding proteins, but the have recently been found to be the cause of ger- Rab6-binding site is in a region next to the car- odermia osteodysplastica, an autosomal reces- boxyl terminus that is shared by both carboxy- sive disorder resulting in osteoporosis and terminal variants (Monier et al. 2002). There wrinkly skin (Hennies et al. 2008). The protein is also a closely related paralog in vertebrates, was found to be localized to the Golgi and to be ERC2, that is exclusively expressed in the brain an effector of Rab6 (and hence the human gene and only exists in a form ending IWA (Hida given the name GORAB). It is conserved in met- and Ohtsuka 2010). azoans, with distant relatives in plants but not Although the proteins have a long coiled- fungi. It contains a stretch of predicted coiled- coil region typical of a golgin, it is less clear coil that is only 150 residues long and is the that the Golgi is their principle location in the most highly conserved part of the protein. cell. ERC2 and the neuronal splice-variants of SCYL1BP1 was first described as a hit from a ERC1 are components of the presynaptic active yeast two-hybrid screen with the inactive pro- zone, and bind via their carboxy-terminal IWA tein kinase Scyl1 (aka NTKL and TEIF) (Di motifs to a PDZ domain in the presynaptic

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protein RIM (Wang et al. 2002). The role of the can cause defects in membrane traffic either nonneuronal splice-variants is less clear, and through the Golgi, or in recycling back from although originally reported to be on the Golgi, endosomes. However these phenotypes, if more recent reports have suggested that they are apparent at all, are usually not a complete block, located to vesicle docking sites on the plasma and sometimes the only obvious phenotype is a membrane (Ohara-Imaizumi et al. 2005; Gri- fragmentation of the Golgi ribbon. In addition, goriev et al. 2007). Invertebrates have a single studies with knockout mice or human genetic ortholog with the C. elegans protein (Elks-1) diseases have shown that loss of the apparen- ending in IWA and being located to the active tly ubiquitously expressed golgins GMAP-210, zone, but mutation causes no phenotype unless TMF, or golgin-160 results in tissue-specific other active zone proteins are also missing defects rather than cell lethality. At a molecular (Deken et al. 2005; Dai et al. 2006). The Droso- level, diverse binding partners have been phila ortholog (Bruchpilot) is awidely used pre- found for particular golgins including kinases, synaptic marker whose deletion causes defects cilia components, and organizers. in synaptic transmission, although its carboxy- However, one striking theme is that many gol- terminal region is different to that of either the gins can bind to small GTPases. In some cases, mammalian proteins (Wagh et al. 2006). these interactions are simply responsible for recruiting the golgin to membranes such as REGULATION OF GOLGIN FUNCTION the binding of Arl1 to the GRIP domains or Rab6 to TMF. However, the first indication An indication of the importance of golgins to that there is potentially more to these interac- the organization of the Golgi is that they are tions came from the finding that golgin-84 targets of modification during and and giantin which have transmembrane do- apoptosis, two processes that involve Golgi frag- mains are nonetheless Rab effectors (Diao mentation. During mitosis, golgin-84 and et al. 2003; Satoh et al. 2003; Rosing et al. GM130 are phosphorylated, and it has been 2007). It has since emerged that the golgins proposed that this alters their interactions and that are recruited by G-proteins binding to their so induces Golgi fragmentation (Lowe et al. carboxyl termini also have Rab-binding sites 1998; Diao et al. 2003; Diao et al. 2008). During along their length (Sinka et al. 2008). In some apoptosis several golgins and associated proteins cases, multiple Rabs can bind to the same gol- are cleaved by caspases, including GM130, gian- gin, and one Rab can bind to multiple golgins tin, golgin-97, and golgin-160 (Mancini et al. including proteins from both cis and trans-ends 2000; Chiu et al. 2002; Nozawa et al. 2002), of the stack. which provides a potential mechanism for the This has lead to the proposal that the indi- associated fragmentation of the Golgi. It has vidual golgins do not have clearly distinct roles, also been found that one golgin, golgin-84, is but rather act collectively to encase the Golgi in cleaved during infection of cells by the bacterial a tentacular cytomatrix studded with binding pathogen Chlamydia, which replicates inside a sites for molecules or structures that need to membrane-bound vacuole (Heuer et al. 2009; associate with the Golgi (Fig. 2). These would Rejman Lipinski et al. 2009). It is thought that include specific proteins such as regulatory the resulting fragmentation of the Golgi is kinases, proteins that interact with the cyto- required for the diversion of lipids and other skeleton, and also larger structures such as nutrients into the replicative vacuole. transport vesicles or even adjacent Golgi stacks. These membrane-bound structures would INTEGRATING THE DIVERSE FUNCTIONS interact via associated Rab G proteins or by OF THE GOLGINS INTO A MODEL other vesicle-associated proteins such as p115, Although the precise functions of the golgins whilst other membranes or large structures remain unclear, several clear themes have such as ribosomes would be excluded. Elec- emerged. At a phenotypic level, their removal tron microscopy studies have indicated that

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The Golgin Coiled-Coil Proteins

Rab binding sites

Rabs

trans

Cytoskeletal interactors

cis

Kinases

Figure 2. A speculative model for golgin function. The golgins surround the Golgi in an array of loosely asso- ciated tentacles. Golgin-specific interactions anchor the proteins via their carboxyl termini to particular parts of the Golgi, but the different golgins share at least some binding partners. This allows cytosolic proteins such as kinases or cytoskeletal interactors to bind to as much of the Golgi stack as is required. Transport vesicles or adjacent cisternae that display activated Rab G proteins are captured by binding directly to Rab binding motifs shared between subsets of golgins. In addition to the Rabs, other vesicle-associated proteins could also contrib- ute to golgin recognition (Nakamura et al. 1997; Jing et al. 2010; Sohda et al. 2010). If the affinity or Rab spe- cificity of these interactions varied through the stack it might direct vesicle movement from sites with a broad distribution (yellow) to those that are restricted to a particular part of the stack (green).

ribosomes are excluded from a zone around the golgins can bind each other and this may help Golgi, whilst the vesicles adjacent to the Golgi hold the golgin cytomatrix together, especially stack are emeshed in elongated structures if transmembrane domain golgins have to enter (Orci et al. 1998; Mogelsvang et al. 2003; Kang retrograde COPI-coated vesiclesto remain in the and Staehelin 2008). Some of these different Golgi (Malsam et al. 2005). types of interactions may need to be dispersed Thus, each golgin could be responsible for over a large part of the stack and so would be multiple types of interaction, of which at least shared with multiple golgins. It is noteworthy some would be shared with other golgins. This that in mammalian cells traffic arriving at the would account not only for the variety of their Golgi from both the ER and endosomal systems interaction partners and of the phenotypes aris- moves along microtubules and so is not directed ing from their removal, but also for the relative to a particular part of the stack. Thus, dispersed mildness of such phenotypes. The golgins seem Rab binding sites would allow capture of incom- to have become longer during the evolution of ing carriers at first contact, and this could per- higher eukaryotes, which may reflect the acqui- haps be refined by more restricted interactions sition of more interaction partners. This model leading to tethering at the correct cisternae. of golgins acting collectively is in some ways There have also been indications that individual analogous to the nucleoporins, which have

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been proposed to collectively fill nuclear pores Barr FA. 1999. A novel Rab6-interacting domain defines a with long unstructured regions that contain family of Golgi-targeted coiled-coil proteins. Curr Biol 9: 381–384. FG repeats to bind importins but act to exclude Barr FA, Nakamura N, Warren G. 1998. Mapping the inter- other proteins (Wa¨lde and Kehlenbach 2010). action between GRASP65 and GM130, components of a Nucleoporins are not coiled-coil proteins, but protein complex involved in the stacking of Golgi cister- it is perhaps notable that similar very large nae. EMBO J 17: 3258–3268. Barr FA, Puype M, Vandekerckhove J, Warren G. 1997. coiled-coil proteins are also found around the GRASP65, a protein involved in the stacking of Golgi cis- centrosome and in the synapse, suggesting ternae. Cell 91: 253–262. that these may also share principles of cytoplas- Barroso M, Nelson DS, Sztul E. 1995. Transcytosis- mic organization with the golgins. associated protein (TAP)/p115 is a general fusion factor required for binding of vesicles to acceptor membranes. Proc Natl Acad Sci 92: 527–531. Bascom RA, Srinivasan S, Nussbaum RL. 1999. Identifica- CONCLUDING REMARKS tion and characterization of golgin-84, a novel Golgi inte- gral membrane protein with a cytoplasmic coiled-coil The golgins are clearly important components domain. J Biol Chem 274: 2953–2962. of the Golgi but their precise functions are still Behnia R, Barr FA, Flanagan JJ, Barlowe C, Munro S. 2007. not clear. Further biochemical and structural The yeast orthologue of GRASP65 forms a complex with a coiled-coil protein that contributes to ER to Golgi traf- studies should reveal more binding partners fic. J Cell Biol 176: 255–261. and the mechanisms by which they recognize Borner GHH, Rana AA, Forster R, Harbour M, Smith JC, the golgins. If it is correct that each golgin can Robinson MS. 2007. CVAK104 is a novel regulator of bind multiple partners then careful analysis clathrin-mediated SNARE sorting. Traffic 8: 893–903. Burguete A, Fenn T, Brunger A, Pfeffer S. 2008. Rab and Arl will be required to dissect the precise role of GTPase family members cooperate in the localization of each interaction. Determining the importance the golgin GCC185. Cell 132: 286–298. of the individual interactions made by a partic- Burman JL, Hamlin JNR, McPherson PS. 2010. Scyl1 regu- ular protein is likely to require the use of genetic lates Golgi morphology. PLoS ONE 5: e9537. systems and the combination of mutants to Cao X, Ballew N, Barlowe C. 1998. Initial docking of ER- derived vesicles requires Uso1p and Ypt1p but is inde- hopefully provide tractable phenotypes. There pendent of SNARE proteins. EMBO J 17: 2156–2165. is clearly much work still to be performed, but Chiu R, Novikov L, Mukherjee S, Shields D. 2002. A caspase the conservation of the proteins and their cleavage fragment of p115 induces fragmentation of the known properties suggest that such studies Golgi apparatus and apoptosis. J Cell Biol 159: 637–648. Conner SD, Schmid SL. 2005. CVAK104 is a novel poly- will reveal much about how the Golgi works. L-lysine-stimulated kinase that targets the b2-subunit of AP2. J Biol Chem 280: 21539–21544. Cruz-Garcia D, Vazquez-Martinez R, Peinado JR, Anouar Y, Tonon MC, Vaudry H, Castan˜o JP, Malagon MM. 2007. ACKNOWLEDGMENTS Identification and characterization of two novel (neuro)- endocrine long coiled-coil proteins. FEBS Lett 581: I would like to thank Francis Barr, Alison Gil- 3149–3156. lingham, Martin Lowe, Franck Perez, Catherine D’Angelo G, Prencipe L, Iodice L, Beznoussenko G, Savarese Rabouille, Rita Sinka, and Graham Warren for M, Marra P, Di Tullio G, Martire G, De Matteis MA, stimulating discussions about golgin function. Bonatti S. 2009. GRASP65 and GRASP55 sequentially promote the transport of C-terminal valine-bearing car- gos to and through the Golgi complex. J Biol Chem 284: 34849–34860. REFERENCES Dai Y,Taru H, Deken SL, Grill B, Ackley B, Nonet ML, Jin Y. 2006. SYD-2 Liprin-a organizes presynaptic active zone An Y,Chen CY,Moyer B, Rotkiewicz P,Elsliger M-A, Godzik formation through ELKS. Nat Neurosci 9: 1479–1487. A, Wilson IA, Balch WE. 2009. Structural and functional Deken SL, Vincent R, Hadwiger G, Liu Q, WangZ-W,Nonet analysis of the globular head domain of p115 provides ML. 2005. Redundant localization mechanisms of insight into membrane tethering. J Mol Biol 391: 26–41. RIM and ELKS in Caenorhabditis elegans. J Neurosci Banu Y,Matsuda M, Yoshihara M, Kondo M, Sutou S, Mat- 25: 5975–5983. sukuma S. 2002. Golgi matrix protein gene, Golga3/ Derby MC, Lieu ZZ, Brown D, Stow JL, Goud B, Gleeson Mea2, rearranged and re-expressed in pachytene sperma- PA. 2007. The trans-Golgi network golgin, GCC185, is tocytes restores spermatogenesis in the mouse. Mol required for endosome-to-Golgi transport and mainte- Reprod Dev 61: 288–301. nance of Golgi structure. Traffic 8: 758–773.

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The Golgin Coiled-Coil Proteins of the Golgi Apparatus

Sean Munro

Cold Spring Harb Perspect Biol 2011; doi: 10.1101/cshperspect.a005256 originally published online March 23, 2011

Subject Collection The Golgi

Structure of Golgi Transport Proteins Golgi and Related Vesicle Proteomics: Simplify to Daniel Kümmel and Karin M. Reinisch Identify Joan Gannon, John J.M. Bergeron and Tommy Nilsson Golgi Biogenesis Organization of SNAREs within the Golgi Stack Yanzhuang Wang and Joachim Seemann Jörg Malsam and Thomas H. Söllner Golgi Glycosylation and Human Inherited Golgi during Development Diseases Weimin Zhong Hudson H. Freeze and Bobby G. Ng Models for Golgi Traffic: A Critical Assessment Entry and Exit Mechanisms at the cis-Face of the Benjamin S. Glick and Alberto Luini Golgi Complex Andrés Lorente-Rodríguez and Charles Barlowe Architecture of the Mammalian Golgi COPI Budding within the Golgi Stack Judith Klumperman Vincent Popoff, Frank Adolf, Britta Brügger, et al. Evolution and Diversity of the Golgi Mechanisms of Protein Retention in the Golgi Mary J. Klute, Paul Melançon and Joel B. Dacks David K. Banfield Evolutionary Forces Shaping the Golgi The Golgin Coiled-Coil Proteins of the Golgi Glycosylation Machinery: Why Cell Surface Apparatus Glycans Are Universal to Living Cells Sean Munro Ajit Varki Golgi Positioning Signaling at the Golgi Smita Yadav and Adam D. Linstedt Peter Mayinger

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