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SHANK Proteins: Roles at the Synapse and in Autism Spectrum Disorder

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SHANK Proteins: Roles at the Synapse and in Autism Spectrum Disorder REVIEWS SHANK proteins: roles at the synapse and in autism spectrum disorder Patricia Monteiro1,2,3,4 and Guoping Feng1,2 Abstract | Several large-scale genomic studies have supported an association between cases of autism spectrum disorder and mutations in the genes SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2 and SHANK3, which encode a family of postsynaptic scaffolding proteins that are present at glutamatergic synapses in the CNS. An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviour. Intragenic promoters During development and throughout life, a number of The SHANK protein family Promoters located within the dynamic processes regulate the number, size, shape and SHANK proteins are ‘master’ scaffolding proteins that body of the residing gene, strength of neuronal synapses. These changes occur tether and organize intermediate scaffolding proteins. regulating its activity. through alterations in the molecular composition of They are located at excitatory synapses, where they are Intragenic promoters are 1,10 mainly active in tissue-specific synapses and through the chemical modification crucial for proper synaptic development and function . 1–4 gene expression. of synaptic proteins . However, sometimes, the genes In the mouse, SHANK proteins are encoded by Shank1, encoding these synaptic proteins (such as those that Shank2 and Shank3 genes. Downstream from their tran­ encode SH3 and multiple ankyrin repeat domains scription start sites, all three genes have alternative pro­ protein 3 (SHANK3), neuroligin 3, neuroligin 4 or moter options, resulting in the generation of a wide array neurexin 1) carry particular mutations that result in of mRNA transcripts and protein isoforms. the production of dysfunctional proteins that cannot fulfil their synaptic role. The consequences of such SHANK3. SHANK3 (also known as ProSAP2) is the 1McGovern Institute for Brain synaptic mutations often affect both protein structure best studied of the three SHANK protein family mem­ Research, Department of and function, leading to synaptic and circuitry defects bers. The Shank3 gene is located on mouse chromosome Brain and Cognitive Sciences, that may have a neurodevelopmental and neuro­ 15E3 (human location: 22q13.3), has 22 exons and spans Massachusetts Institute of (FIG. 1) Technology (MIT), Cambridge, psychiatric impact. 60 kilobases of genomic DNA . Shank3 has mul­ 8,11,12 Massachusetts 02139, USA. Mutations in the SHANK (also known as ProSAP) tiple intragenic promoters (probably six) and several 2Stanley Center for family genes have been linked to syndromic and idio­ alternative splicing exons (exon 11, exon 12, exon 18, exon Psychiatric Research, Broad pathic autism spectrum disorder (ASD), as well as to 21 and exon 22)12, resulting in the possible generation Institute of Massachusetts Institute of Technology (MIT) other neuropsychiatric and neurodevelopmental dis­ of several protein isoforms (see Supplementary infor­ 5–8 and Harvard, Cambridge, orders (schizophrenia and intellectual disability) . In mation S1 (figure)). Besides alternative promoter usage Massachusetts 02142, USA. mice, mutations in the genes encoding SHANK fam­ and mRNA splicing, Shank3 gene expression is regulated 3Life and Health Sciences ily proteins (SHANK1, SHANK2 and SHANK3) often by epigenetic mechanisms such as DNA methylation and Research Institute (ICVS), result in marked behavioural phenotypes. These include histone acetylation, causing tissue­specific expression of School of Health Sciences, 13–15 University of Minho, an increase in repetitive routines, altered social behav­ different SHANK3 isoforms . 4704–553 Braga, Portugal. iour and anxiety­like phenotypes, seemingly similar The full length structure of mouse SHANK3 con­ 4Life and Health Sciences to those described in some human neuro psychiatric tains six domains for protein–protein interactions: Research Institute (ICVS)/3B’s disorders9. according to information contained in the databases PT Government Associate Laboratory, University of Despite great research progress in establishing links UniProt Knowledgebase (UniProtKb) and National Minho, Braga/Guimarães, between mutations in SHANK genes and ASD, the Center for Biotechnology Information (NCBI) database 4710–057 Braga, Portugal. physio logical role of SHANK proteins has, until recently, of the National Library of Medicine at the US National Correspondence to G.F. been poorly understood. Here, we review the most Institutes of Health (see Further information). These [email protected] recent studies that help to clarify the roles of SHANK domains comprise protein domain of unknown func­ doi:10.1038/nrn.2016.183 proteins at the synapse, providing insightful mechanistic tion 535 (DUF535), ankyrin repeat domain, SRC homo­ Published online 9 Feb 2017 links to neuropsychiatric disorders. logy 3 (SH3) domain superfamily, postsynaptic density NATURE REVIEWS | NEUROSCIENCE VOLUME 18 | MARCH 2017 | 147 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS ANK SH3 PDZ PRO SAM Shank1 123 4 5 67 8 9 10 11 12–14 15–17 22 23 24 5 Kb A B 18–21 ANK SH3 PDZ PRO SAM Kb Kb Kb Kb Kb Kb Kb Kb 10 50 20 40 20 60 20 100 Shank2 1 2 3 45 6 7 8 9 10 11 12 13 14 15 16 17–20 21–23 24 25 A B C 10 Kb DUF535 ANK SH3 PDZ PRO SAM Shank3 5 kb 12 3 4–8 9 10 11 12 13–16 17 18 19 20 21 22 A B C D E F Figure 1 | Shank genes: structure and intragenic promoters. The schematics show the fullNature structure Reviews of the | Neurosciencemouse SH3 and multiple ankyrin repeat domains protein (Shank) genes and the location of intragenic promoters within these genes (in the figure, indicated by the arrows with letters in blue boxes). These structures have been drawn on the basis of the information contained at the National Center for Biotechnology Information (NCBI) database and UniProt Knowledgebase (UniProtKb). The location of the protein domains is included above their respective encoding exons (in the figure, exons are numbered and colour coded). Please note that, for the Shank2 gene, some intron sequences have been deleted for simplicity. Each intron deletion is represented by a break symbol of 10 Kb, and the size of each total deletion in Kb is indicated above the respective break. ANK, ankyrin repeat domain; DUF535, protein domain of unknown function 535; PDZ, postsynaptic density protein 95–discs large homologue 1–zonula occludens 1 domain; PRO, proline-rich region; SAM, sterile alpha motif; SH3, SRC homology 3 domain superfamily. protein 95 (PSD95)–discs large homologue 1–zonula five domains: ankyrin repeat domain (located at the occludens 1 (PDZ) domain, proline­rich region (PRO) N terminus), SH3, PDZ, PRO and SAM (located at and sterile alpha motif (SAM). The amino­terminal the C terminus) (FIG. 1). There are three isoforms of ankyrin repeat domain (containing six ankyrin repeats) SHANK2 that are produced by alternative promoter interacts with the PSD protein SHARPIN16 and probably usage: SHANK2E (containing all five protein domains), binds to the cytoskeleton through an interaction with SHANK2A (lacking the ankyrin repeat domain) and spectrin alpha chain, non­erythrocytic 1 (SPTAN1; also SHANK2C (lacking the ankyrin repeat domain and the known as α­fodrin)17. However, the N­terminal region SH3 domain) (see Supplementary information S2 (fig­ that precedes the ankyrin repeat domain interacts intra­ ure)). Another isoform, SHANK2B, is transcribed from molecularly with the six ankyrin repeats and probably the same intragenic promoter as SHANK2A but shows restricts the access to binding partners such as SHARPIN alternative splicing. SHANK2E is the longest isoform and SPTAN1 (REF. 18). The class I PDZ domain of of SHANK2 and is the only isoform that contains the SHANK3 interacts with SAP90/PSD95­associated pro­ ankyrin repeat domain (which is thought to coordinate tein 1 (SAPAP1; also known as GKAP1)10 and the gluta­ actin­dependent events at the apical membrane of epi­ mate receptor 1 (GluR1; also known as GRIA1) subunit thelial cells28). SHANK2E owes its name to the fact that of AMPA receptors (AMPARs)19, which is important it was initially thought to be expressed only in epithe­ for dendritic spine formation and synaptic transmis­ lial cells28; however, recent data suggest that SHANK2E sion. The PRO domain binds to Homer20,21 and cort­ is also expressed in human and mouse brain tissue, Alternative splicing actin10 proteins, which are important for cytoskeleton with high expression levels in the cerebellum29,30. Like A process whereby different mRNAs can be produced from regulation, synaptic transmission and plasticity. Last, SHANK3 and SHANK1, SHANK2 is a scaffolding pro­ a single gene through the the carboxy­terminal SAM domain of SHANK proteins tein of the PSD that interacts with multiple partners at differential incorporation of is known to self­multimerize10,22 and is required for the the synapse10,20,24. exons into the mature localization of SHANK3 and SHANK2 to the PSD23. transcript during splicing. Frequently, various mature Besides all the aforementioned proteins, SHANKs have SHANK1. Shank1 is located on mouse chromosome 8,24–27 proteins are generated from a number of other interaction partners . 7B4 (human location: 19q13.33), has 24 exons and spans a single gene. about 50 Kb of genomic DNA (FIG. 1). The gene contains SHANK2. Shank2 (also known as ProSAP1) is the two different promoters that can generate two differ­ Epigenetic mechanisms largest gene among Shank gene family members and ent protein isoforms: SHANK1A (the longest isoform, A mechanism of a stable change in gene expression that is located on mouse chromosome 7F5 (human loca­ which contains ankyrin repeat domain, SH3, PDZ, PRO does not involve changes in tion: 11q13.2). It has 25 exons and spans about 450 Kb and SAM domains) and SHANK1B (which contains DNA sequence. of mouse genomic DNA (FIG. 1).
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