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Functional Consequences of Mutations in Postsynaptic Scaffolding Proteins and Relevance to Psychiatric Disorders

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Functional Consequences of Mutations in Postsynaptic Scaffolding Proteins and Relevance to Psychiatric Disorders NE35CH03-Ting ARI 12 May 2012 21:39 Functional Consequences of Mutations in Postsynaptic Scaffolding Proteins and Relevance to Psychiatric Disorders Jonathan T. Ting,1,2,∗ Joao˜ Pec¸a,1,∗ and Guoping Feng1,3 1McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; email: [email protected], [email protected], [email protected] 2Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, 27710 3Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts, 02142 Annu. Rev. Neurosci. 2012. 35:49–71 Keywords First published online as a Review in Advance on PSD95, AKAP, SAPAP, Shank, Homer, psychiatric disorders April 20, 2012 The Annual Review of Neuroscience is online at Abstract neuro.annualreviews.org Annu. Rev. Neurosci. 2012.35:49-71. Downloaded from www.annualreviews.org Functional studies on postsynaptic scaffolding proteins at excitatory This article’s doi: synapses have revealed a plethora of important roles for synaptic struc- 10.1146/annurev-neuro-062111-150442 ture and function. In addition, a convergence of recent in vivo func- Access provided by Massachusetts Institute of Technology (MIT) on 06/29/17. For personal use only. Copyright c 2012 by Annual Reviews. tional evidence together with human genetics data strongly suggest that All rights reserved mutations in a variety of these postsynaptic scaffolding proteins may 0147-006X/12/0721-0049$20.00 contribute to the etiology of diverse human psychiatric disorders such ∗These authors contributed equally as schizophrenia, autism spectrum disorders, and obsessive-compulsive spectrum disorders. Here we review the most recent evidence for several key postsynaptic scaffolding protein families and explore how mouse ge- netics and human genetics have intersected to advance our knowledge concerning the contributions of these important players to complex brain function and dysfunction. 49 NE35CH03-Ting ARI 12 May 2012 21:39 INTRODUCTION Contents The Anatomy of the Postsynaptic INTRODUCTION.................. 50 Specialization at Excitatory Synapses The Anatomy of the Postsynaptic The chemical synapse is a microscopic physical Specialization at Excitatory structure that conveys electrical signals from Synapses....................... 50 presynaptic to postsynaptic neurons within Scaffolding Proteins Constitute the brain circuits by means of chemical neuro- Structural Core of the transmitter release and action. Both excitatory PostsynapticDensity............ 50 and inhibitory neurotransmitter release act in PSD95/MAGUK FAMILY. 52 concert under constant fine-tuning to orches- Mutational Analysis of PSD95 trate the flow of information processing in the FamilyFunctionInVivo........ 53 nervous system. Most excitatory synapses are Human Molecular Genetics Data for formed between presynaptic boutons loaded PSD95GeneFamily............ 54 with glutamate-filled synaptic vesicles and AKAPFAMILY...................... 54 tightly apposed protrusions of postsynaptic Mutational Analysis of AKAP79/150 receptor-laden dendritic spines. FunctionInVivo............... 55 The dendritic spine is a highly specialized Human Molecular Genetics Data on structure that is both complex and elegant. AKAP5......................... 56 Electron microscopy images of excitatory HOMERFAMILY................... 57 synapses prominently feature a dense proteina- Mutational Analysis of Homer cious matrix at the tip of the spine head imme- FunctionInVivo............... 58 diately underlying the postsynaptic membrane Human Molecular Genetics Data on face. This protein mesh is called the postsy- Homers........................ 58 naptic density (PSD), and decades of research SAPAPFAMILY..................... 58 using primarily biochemical and molecular Mutational Analysis of SAPAP cloning methods have led to the identification FunctionInVivo............... 59 of many prominent PSD constituents. The Human Molecular Genetics Data on PSD contains many distinct classes of proteins, SAPAPs........................ 59 including neurotransmitter receptors, cell SHANKFAMILY.................... 60 adhesion molecules, ion channels, signaling Mutational Analysis of Shank molecules, and scaffolding proteins (Figure 1). FunctionInVivo............... 61 The dynamic nature and precise topographical Human Molecular Genetics Data on organization of these components give rise to Shanks......................... 62 a supramolecular signal-processing machine. Annu. Rev. Neurosci. 2012.35:49-71. Downloaded from www.annualreviews.org SUMMARY.......................... 63 Deciphering Structural and Functional Roles of Postsynaptic Access provided by Massachusetts Institute of Technology (MIT) on 06/29/17. For personal use only. Scaffolding Proteins at the Scaffolding Proteins Constitute Synapse........................ 63 the Structural Core of the Integration of Human and Mouse Postsynaptic Density Genetics to Elucidate Gene Scaffolding proteins are extremely abundant in Function in Health and the PSD, both in terms of absolute protein copy Disease......................... 63 numbers and the distinct types of scaffolding proteins that have been described to date PSD: postsynaptic (Kim & Sheng 2004, Sheng & Hoogenraad density 2007). The most well-studied postsynaptic scaffolding proteins include members of the 50 Ting · Pec¸a · Feng NE35CH03-Ting ARI 12 May 2012 21:39 Neurexin Neuroligin NMDAR AMPAR Tarp AKAP SAP102 PSD95 PSD93 PSD95 SAP97 SAPAP1/2/3/4 GRIP mGluR Homer1/2/3 SHANK1/2/3 Cortactin N-WASP Actin Figure 1 Scaffolding protein networks at the postsynaptic density (PSD). Schematic of the major family members of PSD scaffolding proteins at excitatory synapses. Current information from structural studies suggests that Shank protein can dimerize through C-terminal sterile alpha motif (SAM) domain–SAM domain interaction and form a supramolecular polymeric network with Homer tetramers. This complex may connect to perisynaptic mGluRs and to synaptic NMDA and AMPA-type ionotropic glutamate receptors through the PSD95 and SAPAP (SAP90/PSD95-associated protein) family of proteins. The Shank/Homer platform may also provide key connection points to the spine actin cytoskeleton. A-kinase anchoring protein (AKAP) is another important protein that can anchor kinases and phosphatases (not shown here) in the vicinity of synaptic receptors and ion channels. Annu. Rev. Neurosci. 2012.35:49-71. Downloaded from www.annualreviews.org PSD95 family, select members of the A-kinase postsynaptic scaffolding proteins can interact anchoring protein (AKAP) family, the Homer with multiple binding partners simultaneously Access provided by Massachusetts Institute of Technology (MIT) on 06/29/17. For personal use only. family, the SAP90/PSD95-associated protein to physically link PSD components and, thus, (SAPAP) family, and the SH3 and multi- can be viewed as the master organizers within ple ankyrin repeat domain (Shank) family. this specialized structure. Scaffolding-protein families are generally Here we aim to highlight evidence from the defined by a highly conserved organization of recent literature concerning the in vivo func- domains for protein-protein interactions, and tional roles served by the major postsynaptic AKAP: A-kinase anchoring protein it is the unique combinations and properties scaffolding protein families. We further exam- of these domains that impart a specificity of ine findings that have emerged from human SAPAP: SAP90/ PSD95-associated protein-protein interactions exhibited by each genetics investigations exploring variations protein of these families (Figure 2). Furthermore, in genes that encode postsynaptic scaffolding www.annualreviews.org • Mutations in Scaffolding Proteins 51 NE35CH03-Ting ARI 12 May 2012 21:39 SYNAPTIC CLEFT AMPAR NMDAR PPSDSD 9955 SSAPAP 9977 PDZ1 AAKAP79/150KAP79/150 PDZ2 PKC binding PDZ3 MAGUK binding SH3–GK SSAPAPAPAP PP2B binding GKAP PKA binding SSHANKHANK ANK SH3 PDZ PLR SAM mGluR HHOMEROMER EVH1 CC2 CC1 CC2 EVH1 DENDRITIC SPINE Figure 2 Physical interactions via discrete binding domains in postsynaptic density (PSD) scaffolding proteins. Representation of the known atomic structures from crystallized domains in key PSD scaffolding proteins, highlighting interactions at known binding sites. For simplicity, protein domains that have not been resolved at the atomic level are displayed in white. Represented domains include the PDZ and SH3 domains of PSD95 and Shank family proteins, the GK domain in PSD95 family proteins, the Ank and SAM domains in Shank family proteins, and the EVH1 and coiled-coil (CC) domains in Homer family proteins (information on these structures was obtained through the RCSB Protein Data Bank http://www.pdb.org). proteins in relation to psychiatric disorders defined PSD95 family of proteins, a subfamily (see Diversity of Human Psychiatric Disorders, of MAGUKs comprised of synapse-associated sidebar below). More comprehensive coverage protein (SAP)102, SAP97, PSD93, and PSD95. Annu. Rev. Neurosci. 2012.35:49-71. Downloaded from www.annualreviews.org MAGUK: of other known PSD scaffolding molecules, These MAGUKs are orthologs of Drosophila membrane-associated particularly with respect to structural con- DLG (discs large), the first cloned MAGUK guanylate kinase siderations, can be found elsewhere (Chen (Woods & Bryant 1991). Access provided by Massachusetts Institute of Technology (MIT) on 06/29/17. For personal use only. Ortholog: genes in et al. 2008, Kim & Sheng 2004, Sheng
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