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Protein Adaptation and the Expanding Roles of the PACS Proteins in Tissue Homeostasis and Disease Gary Thomas1,2,*, Joseph E

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Protein Adaptation and the Expanding Roles of the PACS Proteins in Tissue Homeostasis and Disease Gary Thomas1,2,*, Joseph E © 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 1865-1876 doi:10.1242/jcs.199463 COMMENTARY Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease Gary Thomas1,2,*, Joseph E. Aslan3, Laurel Thomas1, Pushkar Shinde4, Ujwal Shinde4 and Thomas Simmen5 ABSTRACT day ‘one protein – multiple functions’ mantra, which recognizes that Vertebrate proteins that fulfill multiple and seemingly disparate individual proteins often have multiple and seemingly disparate – ‘ ’ functions are increasingly recognized as vital solutions to functions a phenomenon known as moonlighting (Jeffery, 1999; maintaining homeostasis in the face of the complex cell and tissue Henderson and Martin, 2014). The glycolytic enzymes physiology of higher metazoans. However, the molecular adaptations glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and that underpin this increased functionality remain elusive. In this enolase are widely cited examples of moonlighting proteins. Commentary, we review the PACS proteins – which first appeared Human GAPDH participates in as many as 20 different cellular in lower metazoans as protein traffic modulators and evolved in functions ranging from the regulation of membrane traffic to the vertebrates to integrate cytoplasmic protein traffic and interorganellar maintenance of genome integrity (Sirover, 2011). Human enolase communication with nuclear gene expression – as examples of can be present on the cell surface of activated monocytes where it protein adaptation ‘caught in the act’. Vertebrate PACS-1 and PACS-2 serves as a plasminogen receptor that promotes recruitment of increased their functional density and roles as metabolic switches by inflammatory cells to sites of tissue injury (Wygrecka et al., 2009). acquiring phosphorylation sites and nuclear trafficking signals within Protein moonlighting, which by definition is limited to proteins disordered regions of the proteins. These findings illustrate one that use a single primary sequence in the absence of mechanism by which vertebrates accommodate their complex cell posttranslational modifications to mediate multiple functions physiology with a limited set of proteins. We will also highlight how (Jeffery, 1999), is inherently limited for solving evolutionary pathogenic viruses exploit the PACS sorting pathways as well as challenges. Eventually, moonlighting gives way to gene recent studies on PACS genes with mutations or altered expression duplication, which enables the resulting paralogs to acquire that result in diverse diseases. These discoveries suggest that mutations that expand the molecular functions initiated by the investigation of the evolving PACS protein family provides a rich ancestral protein. Inevitably, such a hit-and-miss approach to opportunity for insight into vertebrate cell and organ homeostasis. mutational diversification will hit a roadblock in the form of rigidly folded domains, such as SH2 or PDZ domains found in many proteins (Tompa et al., 2014). The dedicated structure of these Introduction ∼100-amino-acid protein domains, which are typically involved in At the turn of the 20th century, Archibald Garrod, Walter Sutton and high-affinity binding to discrete ligands, limits amino acid Thomas Hunt Morgan ushered in a new era of biological research by substitutions, thereby reducing their ability to increase the replacing observational studies with mechanistic analyses (Kelves functional density of associated cellular proteins. Therefore, and Hood, 1992). Their discoveries that chromosomes encode protein adaptation represents an additional and vital solution to heritable traits set the foundation for understanding genetic increase the array of protein functions to an extent that is not inheritance. More than 30 years later, through inactivation and possible by moonlighting and gene duplication alone (Tompa et al., mutational studies of the common bread mold Neurospora, George 2014). Rather than coaxing rigid protein domains to accept new Beadle and Edward Tatum ultimately determined that genes encode roles, such proteins – notably vertebrate proteins – have acquired enzymes and laid a cornerstone of modern molecular biology intrinsically disordered regions (IDRs) to complement the limited through the ‘one gene – one protein’ hypothesis (Beadle and Tatum, utility of folded domains (Dunker et al., 2005; Pancsa and Tompa, 1941). This provocative model inevitably collapsed under the 2016). IDRs do not fold into an autonomous structure, but contain weight of subsequent discoveries, which revealed that genes flexible 5–15-amino-acid small linear motifs (SLiMs) that can frequently encode multiple proteins or collections of peptides that assume an ensemble of ‘structures’, which in turn interact with a drive complex physiology and contribute to molecular promiscuity panoply of binding partners through low-affinity but high- through mechanisms ranging from alternative RNA splicing to the specificity interactions (Davey et al., 2015). SLiMs are frequently proteolytic processing of polyproteins (‘one gene – many proteins’; sites of posttranslational modifications and undergo rapid evolution, Yang et al., 2016). The essence of these studies led to the present- greatly increasing the functional density of IDR-containing proteins (Tompa et al., 2014; Pancsa and Tompa, 2016). This plasticity enabled SLiMs from disparate proteins across a large taxonomic 1Department of Microbiology and Molecular Genetics, University of Pittsburgh range to acquire similar amino acid mutations by convergent School of Medicine, Pittsburgh, PA 15239, USA. 2University of Pittsburgh Cancer Institute, Pittsburgh, PA 15239, USA. 3Knight Cardiovascular Institute, Oregon evolution so that they may bind to a common globular protein Health & Science University, Portland, OR 97239, USA. 4Department of domain (Schlessinger et al., 2011; Davey et al., 2012, 2015; Van Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA. 5Department of Cell Biology, University of Alberta, Edmonton, Roey et al., 2012; Jonas and Izaurralde, 2013). However, examples Alberta, Canada T6G2H7. tracing how a single protein adapted to evolutionary pressure by acquiring specific SLiM mutations in order to fulfill new functions *Author for correspondence ([email protected]) that are critical for vertebrate homeostasis are surprisingly limited. G.T., 0000-0003-1976-7183 Studies on the phosphofurin acidic cluster sorting (PACS) proteins Journal of Cell Science 1865 COMMENTARY Journal of Cell Science (2017) 130, 1865-1876 doi:10.1242/jcs.199463 provide a powerful illustration of such evolutionary protein appearance of the vertebrates, resulting in the PACS-1 and PACS-2 adaptations ‘caught in the act’ of connecting the increasingly genes. complex organellar landscape that underpins vertebrate cell The regulation of membrane traffic remains a role that is function. conserved among the vertebrate PACS proteins. The PACS-1 FBR Here, we discuss how PACS proteins first appeared in metazoans binds to acidic clusters that can be phosphorylated by casein kinase as membrane traffic regulators, and then expanded their functional 2 (CK2), as well as α-helices on a large number of client proteins repertoire in vertebrates by acquiring molecular switches, notably (Wan et al., 1998; Youker et al., 2009; Dikeakos et al., 2012). Thus, phosphorylation sites and nuclear localization signals (NLSs) PACS-1, which interacts with the clathrin adaptors AP-1 and AP-3, within their SLiMs. These gain-of-function adaptations enabled as well as the monomeric adaptor GGA3, mediates localization of the vertebrate PACS proteins to integrate cytoplasmic functions furin and other client proteins to the trans-Golgi network (TGN) and with nuclear gene expression. In particular, we focus on the also targets a subset of client proteins to the primary cilium, acquisition of an Akt phosphorylation site and NLS in vertebrate including the adaptor protein nephrocystin (also known as NPHP1) PACS-2, which enable this protein to function as a metabolic switch and the olfactory cyclic-nucleotide-gated ion channel (CNG), the that integrates cytoplasmic membrane traffic and interorganellar latter by binding to the β1 subunit (CNGB1) (Fig. 3A) (Wan et al., communication with nuclear gene expression in response to 1998; Schermer et al., 2005; Jenkins et al., 2009; Youker et al., anabolic or catabolic cues. 2009). PACS-1 acquired a CK2-phosphorylated acidic cluster of its own, which is located in the disordered MR (see Fig. 1). CK2 PACS proteins direct membrane trafficking in worms to phosphorylation of Ser278 in the PACS-1 autoregulatory domain humans controls intramolecular binding to the FBR, which regulates the The PACS proteins were discovered in a genetic screen for interaction with client proteins (Scott et al., 2003). PACS-2, which regulators of the secretory pathway proteinase furin (Wan et al., interacts with the coatomer COPI, mediates the localization of cargo 1998; Thomas, 2002). Human PACS1 is located at 11q13.1-q13.2 to the endoplasmic reticulum (ER) and, similar to cePACS, directs and contains 24 exons and at least 12 alternatively spliced variants. trafficking from early endosomes (Youker et al., 2009) (Fig. 3A, see Human PACS-2, which is located near the telomere at 14q32.33, also Fig. 4A). PACS-2 stabilizes a pool of the metalloproteinase also contains 24 exons and at least 11 alternatively spliced variants. ADAM17
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