Shank protein

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Revision as of 23:02, 28 February 2011

Shank Family Proteins are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines that is associated with the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors, signaling pathways, and regulatory elements within a cytoskeletal matrix.^[1] It aids the appropriate communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural activity.^[2] Shank proteins are believed to function as master organizer of the PSD owing to their ability to recruit and form multimeric complexes with postsynaptic receptors, signaling molecules and cytoskeletal proteins like AMPA, Neuroligin and NMDA glutamate receptors.^[3] Within the PSD, there are over 300 individual shank molecules in a single postsynaptic site, representing 5% of the total protein molecules and total protein mass of the PSD.^[4] Shanks contain five domains for protein-protein interactions, including an ankyrin repeat domain, used to bind acting regulating proteins, an Src homology 3 (Sh3) domain, used to bind AMPA receptors, a PDZ domain, used to bind G protein coupled receptors, several proline-rich domains , and a C-terminal SAM domain, which is responsible for mediating Shank multimerization.^[1] Functionally, Shank is involved in the maturation and enlargement of dendritic spines and is able to induce spine formation in neurons.^[3]

Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and autism spectrum disorder features.^[3] The SHANK3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in SHANK3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of autism cases.^[5] At the molecular level, disruption of the full length Shank3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.^[4] Shank3 heterozygous mice, who are haploinsufficient for the Shank3 gene display less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of SHANK3 may also result in an ASD, supporting the hypothesis that Autism is caused by improper Excitatory/Inhibitory neuronal ratios in the brain.^[4] Measurements of broad miRNA expression levels in Autism patients uncovered dysregulated miRNAs for genes like that of MeCP2, the cause of Rett Syndrome, NRXN-1, a gene implicated in ASDs, and Shank3, validating Shank3’s role in autism.^[6] Due to the marked reduction in AMPA mediated transmission in Shank3 mutants, compounds that enhance AMPA transmission (AMPAkinses) as potential therapeutic approaches to treating some ASDs.^[4] BetaPIX belongs to a group of guanine nucleotide exchange factors used by Rho GTPase family members, like Rac1 and Cdc42, which are known to regulate the actin cytoskeleton of synapses.^[7] PIX has an N-terminal Src homology 3 (SH3) domain which associates with PAK, a coiled-coil (CC) domain, which is critical for multimerization, and a C-terminal PDZ binding domain which interacts with the PDZ domain of Shank.^[7] The interaction of Shank with betaPIX promotes the synaptic localization of betaPIX and betaPIX associated p21 Associated Kinase (PAK). Since PAK is known to regulate the actin cytoskeleton and that dendritic spines are actin-rich structures, it is believed that Shank recruits betaPIX and associated proteins to spines and regulates postsynaptic structure.^[1]

The **canonical PDZ domain** contains 90 amino acids and folds into a compact **globular structure** consisting of a six-stranded beta-sandwich flanked by two alpha helices.^[7] BetaPIX forms a **parallel trimer** via its CC domain with a **PDZ binding domain** at the C-terminus. Interestingly, only 1 Shank molecule is bound to the CC domain trimer of betaPIX in an **asymettric assembly**. (SHOW ZOOMED OUT IN SPACE FILL WITH LONG PART DIRECTLY VERTICAL) The **8-residue PDZ binding domain** (BALL AND STICK AND SPHERE COMBO BURIED MODE) of BetaPIX forms a number of **hydrogen bonding and hydrophobic interactions** (FIGURE 2A) with the Shank PDZ domain. Shank3-Arg 679 forms the **most critical interaction** with BetaPIX, tightly binding Glutamate -3. Abolishing this interaction through mutagenesis completely eliminates the assembly. Upon binding of betaPIX, the PDZ domain undergoes a significant **conformational change** (OVERVIEW MORPH). Lys 682 undergoes a nearly **11 Angstrom displacement**, ultimately forming a **beta-sheet interaction**, with betaPIX residues -4--6, incorporating Shank residues 680 and 681.^[7]

Shank proteins are wedged between scaffolding proteins that are bound to either neurotransmitter receptors or the actin cytoskeleton, making them well positioned to nucleate the underlying structure of the PSD.^[2] The SAM domain of **Shank3 can oligomerize** to form large sheets composed of helical fibers stacked side by side. The proposed sheet structure with radially projecting protein interaction domains, appears to be an ideal architecture for a protein that must contact both membrane and cytoplasmic components at a cell surface. A number of hydrogen bonding and hydrophobic interactions stabilize the **intra-polymer** interface and the inter-polymer interfaces, labeled **contact 1** and **contact 2**.^[2] Models of this sort validate the importance of Shank3 as master scaffolding proteins and illustrate how slight mutations can disrupt an entire PSD and synaptic function.

Additional Structures of Shank Family Proteins

References

↑ ^1.0 ^1.1 ^1.2 Park E, Na M, Choi J, Kim S, Lee JR, Yoon J, Park D, Sheng M, Kim E. The Shank family of postsynaptic density proteins interacts with and promotes synaptic accumulation of the beta PIX guanine nucleotide exchange factor for Rac1 and Cdc42. J Biol Chem. 2003 May 23;278(21):19220-9. Epub 2003 Mar 7. PMID:12626503 doi:10.1074/jbc.M301052200
↑ ^2.0 ^2.1 ^2.2 Baron MK, Boeckers TM, Vaida B, Faham S, Gingery M, Sawaya MR, Salyer D, Gundelfinger ED, Bowie JU. An architectural framework that may lie at the core of the postsynaptic density. Science. 2006 Jan 27;311(5760):531-5. PMID:16439662 doi:311/5760/531
↑ ^3.0 ^3.1 ^3.2 Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007 Jan;39(1):25-7. Epub 2006 Dec 17. PMID:17173049 doi:ng1933
↑ ^4.0 ^4.1 ^4.2 ^4.3 Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML, Harris MJ, Saxena R, Silverman JL, Crawley JN, Zhou Q, Hof PR, Buxbaum JD. Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism. 2010 Dec 17;1(1):15. PMID:21167025 doi:10.1186/2040-2392-1-15
↑ Garber K. Neuroscience. Autism's cause may reside in abnormalities at the synapse. Science. 2007 Jul 13;317(5835):190-1. PMID:17626859 doi:10.1126/science.317.5835.190
↑ Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, Lao K, Kosik KS. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics. 2008 Jul;9(3):153-61. Epub 2008 Jun 19. PMID:18563458 doi:10.1007/s10048-008-0133-5
↑ ^7.0 ^7.1 ^7.2 ^7.3 Im YJ, Kang GB, Lee JH, Park KR, Song HE, Kim E, Song WK, Park D, Eom SH. Structural basis for asymmetric association of the betaPIX coiled coil and shank PDZ. J Mol Biol. 2010 Mar 26;397(2):457-66. Epub 2010 Jan 29. PMID:20117114 doi:10.1016/j.jmb.2010.01.048

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-	<StructureSection load='' size='500' side='right' caption='Structure of Shank Family Proteins, [[]]' scene=''>	+	<StructureSection load='3l4f' size='500' side='right' caption='Structure of Shank Family Proteins, [[3l4f]]' scene='Shank_Family_Proteins/Opening/1'>
	[[Image:Shank Schematic.png\|150px\|left]]      [[Shank Family Proteins]] are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines that is associated with the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors, signaling pathways, and regulatory elements within a cytoskeletal matrix.<ref name="Park">PMID:12626503</ref> It aids the appropriate communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural activity.<ref name="Baron">PMID:16439662</ref> Shank proteins are believed to function as master organizer of the PSD owing to their ability to recruit and form multimeric complexes with postsynaptic receptors, signaling molecules and cytoskeletal proteins like AMPA, [[Neuroligin-Neurexin Interaction\|Neuroligin]] and NMDA glutamate receptors.<ref name="Durand">PMID:17173049</ref> Within the PSD, there are over 300 individual shank molecules in a single postsynaptic site, representing 5% of the total protein molecules and total protein mass of the PSD.<ref name="Bozdagi">PMID: 21167025</ref> Shanks contain five domains for protein-protein interactions, including an ankyrin repeat domain, used to bind acting regulating proteins, an Src homology 3 (Sh3) domain, used to bind AMPA receptors, a PDZ domain, used to bind G protein coupled receptors, several proline-rich domains , and a C-terminal SAM domain, which is responsible for mediating Shank multimerization.<ref name="Park"/> Functionally, Shank is involved in the maturation and enlargement of dendritic spines and is able to induce spine formation in neurons.<ref name="Durand"/>		[[Image:Shank Schematic.png\|150px\|left]]      [[Shank Family Proteins]] are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines that is associated with the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors, signaling pathways, and regulatory elements within a cytoskeletal matrix.<ref name="Park">PMID:12626503</ref> It aids the appropriate communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural activity.<ref name="Baron">PMID:16439662</ref> Shank proteins are believed to function as master organizer of the PSD owing to their ability to recruit and form multimeric complexes with postsynaptic receptors, signaling molecules and cytoskeletal proteins like AMPA, [[Neuroligin-Neurexin Interaction\|Neuroligin]] and NMDA glutamate receptors.<ref name="Durand">PMID:17173049</ref> Within the PSD, there are over 300 individual shank molecules in a single postsynaptic site, representing 5% of the total protein molecules and total protein mass of the PSD.<ref name="Bozdagi">PMID: 21167025</ref> Shanks contain five domains for protein-protein interactions, including an ankyrin repeat domain, used to bind acting regulating proteins, an Src homology 3 (Sh3) domain, used to bind AMPA receptors, a PDZ domain, used to bind G protein coupled receptors, several proline-rich domains , and a C-terminal SAM domain, which is responsible for mediating Shank multimerization.<ref name="Park"/> Functionally, Shank is involved in the maturation and enlargement of dendritic spines and is able to induce spine formation in neurons.<ref name="Durand"/>

Shank protein

From Proteopedia

Revision as of 23:02, 28 February 2011

Additional Structures of Shank Family Proteins

References

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