Shank protein: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
David Canner (talk | contribs)
7,699 edits
No edit summary
David Canner (talk | contribs)
7,699 edits
No edit summary
Line 2: Line 2:
[[Image:Shank Schematic.png|150px|left]]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; [[Shank Family Proteins]] are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines and within the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors and regulatory elements within a cytoskeletal matrix.<ref name="Park">PMID:12626503</ref> It coordinates communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural signals.<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, representing 5% of the total protein molecules within 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. (See Image)<ref name="Park"/> Functionally, Shank is involved in the maturation of dendritic spines and is able to induce spine formation in neurons.<ref name="Durand"/>
[[Image:Shank Schematic.png|150px|left]]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; [[Shank Family Proteins]] are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines and within the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors and regulatory elements within a cytoskeletal matrix.<ref name="Park">PMID:12626503</ref> It coordinates communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural signals.<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, representing 5% of the total protein molecules within 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. (See Image)<ref name="Park"/> Functionally, Shank is involved in the maturation of dendritic spines and is able to induce spine formation in neurons.<ref name="Durand"/>


====Chromosome 22q13 Deletion Syndrome====
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and [[Neurodevelopmental Disorders|autism spectrum disorder (ASD)]] features.<ref name="Durand"/> The Shank-3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in Shank-3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of all autism cases.<ref name="Garber">PMID: 17626859</ref> At the molecular level, disruption of the full length Shank-3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.<ref name="Bozdagi"/> Shank-3 heterozygous mice, who are haploinsufficient for the Shank-3 gene emitted fewer ultrasonic vocalizations during interactions with estrus female mice, a behavior reminiscent of that seen in Autism patients. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of proteins GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of Shank-3 may also result in an ASD, supporting the hypothesis that Autism is caused by improper Excitatory/Inhibitory neuronal ratios in the brain.<ref name="Bozdagi"/> Measurements of  broad miRNA expression levels in Autism patients uncovered dysregulated miRNAs for genes involved in ASDs like [[MeCP2]], the cause of Rett Syndrome, [[Neurexin-Neuroligin Interaction|NRXN-1]], a gene implicated in ASDs, and Shank-3, validating Shank-3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA mediated transmission in Shank-3 mutants, compounds that enhance AMPA transmission (AMPAkinses) serve as potential [[Pharmaceutical Drugs|therapeutic approaches]] to treating some ASDs.<ref name="Bozdagi"/>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and [[Neurodevelopmental Disorders|autism spectrum disorder (ASD)]] features.<ref name="Durand"/> The Shank-3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in Shank-3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of all autism cases.<ref name="Garber">PMID: 17626859</ref> At the molecular level, disruption of the full length Shank-3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.<ref name="Bozdagi"/> Shank-3 heterozygous mice, who are haploinsufficient for the Shank-3 gene emitted fewer ultrasonic vocalizations during interactions with estrus female mice, a behavior reminiscent of that seen in Autism patients. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of proteins GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of Shank-3 may also result in an ASD, supporting the hypothesis that Autism is caused by improper Excitatory/Inhibitory neuronal ratios in the brain.<ref name="Bozdagi"/> Measurements of  broad miRNA expression levels in Autism patients uncovered dysregulated miRNAs for genes involved in ASDs like [[MeCP2]], the cause of Rett Syndrome, [[Neurexin-Neuroligin Interaction|NRXN-1]], a gene implicated in ASDs, and Shank-3, validating Shank-3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA mediated transmission in Shank-3 mutants, compounds that enhance AMPA transmission (AMPAkinses) serve as potential [[Pharmaceutical Drugs|therapeutic approaches]] to treating some ASDs.<ref name="Bozdagi"/>


====βPIX Structure====
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;βPIX 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.<ref name="IM">PMID: 20117114</ref> 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.<ref name="IM"/> The interaction of Shank with βPIX promotes the synaptic localization of βPIX and βPIX associated p21 Associated Kinase (PAK). Since PAK is known to regulate actin cytoskeletons and dendritic spines are actin-rich structures, it is believed that Shank recruits βPIX and associated proteins to spines to regulate the PSD.<ref name="Park"/>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;βPIX 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.<ref name="IM">PMID: 20117114</ref> 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.<ref name="IM"/> The interaction of Shank with βPIX promotes the synaptic localization of βPIX and βPIX associated p21 Associated Kinase (PAK). Since PAK is known to regulate actin cytoskeletons and dendritic spines are actin-rich structures, it is believed that Shank recruits βPIX and associated proteins to spines to regulate the PSD.<ref name="Park"/>


====Shank Family Protein Structure====
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The <scene name='Shank_Family_Proteins/Pdz/1'>canonical PDZ domain</scene> contains 90 amino acids and folds into a compact <scene name='Shank_Family_Proteins/Pdz_glob/1'>globular structure</scene> consisting of a six-stranded β-sandwich flanked by two alpha helices.<ref name="IM"/> βPIX possess a <scene name='Shank_Family_Proteins/Bpix_trimer/2'>parallel trimer</scene> via <scene name='Shank_Family_Proteins/Bpix_phob/1'>helical hydrophobic interactions</scene> within its CC domain, a <scene name='Shank_Family_Proteins/Proline/1'>proline to break the helix</scene>, and a <scene name='Shank_Family_Proteins/Pdz_binding/1'>PDZ binding domain</scene> at the C-terminus. Interestingly, only 1 Shank molecule is bound to the CC domain trimer of βPIX in an <scene name='Shank_Family_Proteins/Asym/1'>asymettric assembly</scene>. The <scene name='Shank_Family_Proteins/Bubble/1'>8-residue PDZ binding domain</scene> of βPIX forms a number of <scene name='Shank_Family_Proteins/Inter/1'>hydrogen bonding and hydrophobic interactions</scene> with the Shank PDZ domain.  Shank-3-Arg 679 forms the <scene name='Shank_Family_Proteins/Arg/2'>most critical interaction</scene> with βPIX, tightly H-Bonding Glutamate 643, forming 2 weak bonds with Phe 696, and Van der Waals interactions with ring of Phe 696. Abolishing this interaction through mutagenesis completely eliminates the assembly. Upon binding of βPIX, the PDZ domain undergoes a significant <scene name='Shank_Family_Proteins/Morph_overview/4'>conformational change</scene>.  Lys 682 undergoes a nearly <scene name='Shank_Family_Proteins/Morph_lys/3'>11 Angstrom displacement</scene> to make room for the βPIX PDZ binding domain.<ref name="IM"/>
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The <scene name='Shank_Family_Proteins/Pdz/1'>canonical PDZ domain</scene> contains 90 amino acids and folds into a compact <scene name='Shank_Family_Proteins/Pdz_glob/1'>globular structure</scene> consisting of a six-stranded β-sandwich flanked by two alpha helices.<ref name="IM"/> βPIX possess a <scene name='Shank_Family_Proteins/Bpix_trimer/2'>parallel trimer</scene> via <scene name='Shank_Family_Proteins/Bpix_phob/1'>helical hydrophobic interactions</scene> within its CC domain, a <scene name='Shank_Family_Proteins/Proline/1'>proline to break the helix</scene>, and a <scene name='Shank_Family_Proteins/Pdz_binding/1'>PDZ binding domain</scene> at the C-terminus. Interestingly, only 1 Shank molecule is bound to the CC domain trimer of βPIX in an <scene name='Shank_Family_Proteins/Asym/1'>asymettric assembly</scene>. The <scene name='Shank_Family_Proteins/Bubble/1'>8-residue PDZ binding domain</scene> of βPIX forms a number of <scene name='Shank_Family_Proteins/Inter/1'>hydrogen bonding and hydrophobic interactions</scene> with the Shank PDZ domain.  Shank-3-Arg 679 forms the <scene name='Shank_Family_Proteins/Arg/2'>most critical interaction</scene> with βPIX, tightly H-Bonding Glutamate 643, forming 2 weak bonds with Phe 696, and Van der Waals interactions with ring of Phe 696. Abolishing this interaction through mutagenesis completely eliminates the assembly. Upon binding of βPIX, the PDZ domain undergoes a significant <scene name='Shank_Family_Proteins/Morph_overview/4'>conformational change</scene>.  Lys 682 undergoes a nearly <scene name='Shank_Family_Proteins/Morph_lys/3'>11 Angstrom displacement</scene> to make room for the βPIX PDZ binding domain.<ref name="IM"/>


====Shank Oligomerization====
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Shank proteins are positioned between scaffolding proteins that are bound to either neurotransmitter receptors or the actin cytoskeleton. This puts Shank proteins in a perfect position to nucleate the underlying structure of the PSD.<ref name="Baron"/> The SAM domain of <scene name='Shank_Family_Proteins/Multimer_opening/1'>Shank-3 can oligomerize</scene> (<scene name='Shank_Family_Proteins/Multimer_opening_alt/2'>Alternate View</scene>) to form large sheets composed of helical fibers stacked side by side. The proposed sheet structure with radially projecting protein interaction domains, is ideal architecture for a protein that must contact both membrane and cytoplasmic components at a synaptic surface.<ref name="Baron"/>  Models of this sort validate the importance of Shank-3 as master scaffolding proteins and illustrate how slight mutations can disrupt an entire PSD and synaptic function.
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Shank proteins are positioned between scaffolding proteins that are bound to either neurotransmitter receptors or the actin cytoskeleton. This puts Shank proteins in a perfect position to nucleate the underlying structure of the PSD.<ref name="Baron"/> The SAM domain of <scene name='Shank_Family_Proteins/Multimer_opening/1'>Shank-3 can oligomerize</scene> (<scene name='Shank_Family_Proteins/Multimer_opening_alt/2'>Alternate View</scene>) to form large sheets composed of helical fibers stacked side by side. The proposed sheet structure with radially projecting protein interaction domains, is ideal architecture for a protein that must contact both membrane and cytoplasmic components at a synaptic surface.<ref name="Baron"/>  Models of this sort validate the importance of Shank-3 as master scaffolding proteins and illustrate how slight mutations can disrupt an entire PSD and synaptic function.
</StructureSection>
</StructureSection>

Revision as of 07:20, 13 March 2011

      Shank Family Proteins are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within dendritic spines and within the postsynaptic membrane, contains a complex assembly of proteins which organize neurotransmitter receptors and regulatory elements within a cytoskeletal matrix.[1] It coordinates communication of incoming signals to cytoplasmic targets and contributes to neuronal plasticity by readily changing its composition and structure in response to neural signals.[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, representing 5% of the total protein molecules within 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. (See Image)[1] Functionally, Shank is involved in the maturation of dendritic spines and is able to induce spine formation in neurons.[3]

Chromosome 22q13 Deletion Syndrome

     Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by neonatal hyptonia, global developmental delay, and autism spectrum disorder (ASD) features.[3] The Shank-3 gene is located within this region of chromosome 22. Studies have revealed that point mutations in Shank-3 can produce the entirety of neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of all autism cases.[5] At the molecular level, disruption of the full length Shank-3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.[4] Shank-3 heterozygous mice, who are haploinsufficient for the Shank-3 gene emitted fewer ultrasonic vocalizations during interactions with estrus female mice, a behavior reminiscent of that seen in Autism patients. Further, knockout mice of Shank have a decreased spine number, a diminished PSD size, decreased levels of proteins GKAP and Homer, and reduced synaptic transmission. Interestingly, overexpression of Shank-3 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 involved in ASDs like MeCP2, the cause of Rett Syndrome, NRXN-1, a gene implicated in ASDs, and Shank-3, validating Shank-3’s role in autism.[6] Due to the marked reduction in AMPA mediated transmission in Shank-3 mutants, compounds that enhance AMPA transmission (AMPAkinses) serve as potential therapeutic approaches to treating some ASDs.[4]

βPIX Structure

     βPIX 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 βPIX promotes the synaptic localization of βPIX and βPIX associated p21 Associated Kinase (PAK). Since PAK is known to regulate actin cytoskeletons and dendritic spines are actin-rich structures, it is believed that Shank recruits βPIX and associated proteins to spines to regulate the PSD.[1]

Shank Family Protein Structure

     The contains 90 amino acids and folds into a compact consisting of a six-stranded β-sandwich flanked by two alpha helices.[7] βPIX possess a via within its CC domain, a , and a at the C-terminus. Interestingly, only 1 Shank molecule is bound to the CC domain trimer of βPIX in an . The of βPIX forms a number of with the Shank PDZ domain. Shank-3-Arg 679 forms the with βPIX, tightly H-Bonding Glutamate 643, forming 2 weak bonds with Phe 696, and Van der Waals interactions with ring of Phe 696. Abolishing this interaction through mutagenesis completely eliminates the assembly. Upon binding of βPIX, the PDZ domain undergoes a significant . Lys 682 undergoes a nearly to make room for the βPIX PDZ binding domain.[7]

Shank Oligomerization

     Shank proteins are positioned between scaffolding proteins that are bound to either neurotransmitter receptors or the actin cytoskeleton. This puts Shank proteins in a perfect position to nucleate the underlying structure of the PSD.[2] The SAM domain of () to form large sheets composed of helical fibers stacked side by side. The proposed sheet structure with radially projecting protein interaction domains, is ideal architecture for a protein that must contact both membrane and cytoplasmic components at a synaptic surface.[2] Models of this sort validate the importance of Shank-3 as master scaffolding proteins and illustrate how slight mutations can disrupt an entire PSD and synaptic function.

Structure of Shank Family Proteins, 3l4f

Drag the structure with the mouse to rotate

Additional Structures of Shank Family ProteinsAdditional Structures of Shank Family Proteins

2fn3 - Crystal Structure of the native Shank SAM domain
2f44 - Crystal Structure of the Zinc-bound Shank SAM domain
1q3o, 1q3p - Crystal structure of the Shank PDZ-ligand complex

ReferencesReferences

  1. ↑ 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. ↑ 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. ↑ 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. ↑ 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
  5. ↑ 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
  6. ↑ 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. ↑ 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

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

David Canner, Michal Harel, Alexander Berchansky, Joel L. Sussman
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=Shank_protein&oldid=1203765"