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<StructureSection load='3l4f' size='500' side='right' caption='Structure of Shank Family Proteins, [[3l4f]]' scene='Shank_Family_Proteins/Opening/1'>
<StructureSection load='' size='350' side='right' caption='Structure of rat Shank1 protein PDZ domain trimer complex with guanine nucleotide exchange factor 7 C terminal (yellow), [[3l4f]]' scene='Shank_Family_Proteins/Opening/1'>
[[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"/>
__TOC__
[[Image:Shank Schematic.png|150px|left]]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; '''Shank (SH3 and multiple ankyrin repeat domains protein) Family Proteins''' are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within the postsynaptic membrane of dendritic spines, contains a complex assembly of proteins which organize neurotransmitter receptors and regulatory elements.<ref name="Park">PMID:12626503</ref> The PSD coordinates communication of incoming signals to various targets and changes its composition in response to neural signals to aid neuronal plasticity<ref name="Baron">PMID:16439662</ref> Shank proteins function as the master organizer of the PSD with 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|glutamate receptors]].<ref name="Durand">PMID:17173049</ref>  Within the PSD, there are over 300 individual shank molecules, roughly  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"/> Shank also mediates the maturation of dendritic spines in neurons.<ref name="Durand"/> See also [[Neurodevelopmental Disorders]].
*'''SHANK1''' mutations were detected in individuals with autism spectrum disorders<ref>PMID:26335738</ref>.
*'''SHANK2''' is located at the postsynaptic membrane of glutamatergic neurons<ref>PMID:32987185</ref>.
*'''SHANK3''' is enriched at the postsynaptic density of excitatory synapses<ref>PMID:22749736</ref>.


&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 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 all autism cases.<ref name="Garber">PMID: 17626859</ref> At the molecular level, disruption of the full length Shank3 protein results in reductions in AMPA receptor mediated transmission and spine remodeling.<ref name="Bozdagi"/> Shank3 heterozygous mice, who are haploinsufficient for the Shank3 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 SHANK3 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 Shank3, validating Shank3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA mediated transmission in Shank3 mutants, compounds that enhance AMPA transmission (AMPAkinses) serve as potential [[Pharmaceutical Drugs|therapeutic approaches]] to treating some ASDs.<ref name="Bozdagi"/>
====Chromosome 22q13 Deletion Syndrome====
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by 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 cause the 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 reduces AMPA receptor signaling and spine remodeling.<ref name="Bozdagi"/>Mice who were haploinsufficient for Shank-3, emitted fewer ultrasonic vocalizations during interactions with estrus female mice, a behavior reminiscent of that seen in Autism patients. Further, Shank knockout mice have less dendritic spine development, a diminished PSD size, decreased levels of proteins GKAP and Homer, and greatly impaired synaptic signaling. 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 aberrant levels of 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, adding support to Shank-3’s role in autism.<ref>PMID:18563458</ref> Due to the marked reduction in AMPA receptor signalling 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;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"/>
====βPIX Structure====
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;βPIX is a protein belonging to a group of guanine nucleotide exchange factors used by Rho GTPase family members, like Rac1 and Cdc42. Rac1 and Cdc42 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 regulates actin cytoskeletons, and dendritic spines are actin-rich structures, it is believed that Shank recruits βPIX to dendritic spines to regulate the PSD.<ref name="Park"/>


&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.  Shank3-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 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;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'>Shank3 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 Shank3 as master scaffolding proteins and illustrate how slight mutations can disrupt an entire PSD and synaptic function.
====Shank Oligomerization====
</StructureSection>
&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 create the underlying structure of the PSD.<ref name="Baron"/> The <scene name='Shank_Family_Proteins/Multimer_opening_single/1'>SAM domain</scene> of Shank-3 can <scene name='Shank_Family_Proteins/Multimer_opening/2'>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"/>  It resembles the structure of a peg board, with Shank oligomers forming the board and PIX proteins forming the pegs to which things attach. 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.
__NOTOC__
__NOEDITSECTION__
 
 
==Page Development==
This article was developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University.
 
==3D structures of Shank Family Proteins==
 
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}


==Additional Structures of Shank Family Proteins==
[[6cpi]] – hSHK1 SH3 domain – human - NMR<br />
[[2fn3]] - Crystal Structure of the native Shank SAM domain <br/>
[[1q3o]] – rSHK1 PDZ domain – rat<br />
[[2f44]] - Crystal Structure of the Zinc-bound Shank SAM domain <br/>
[[1q3p]] – rSHK1 PDZ domain + guanylate kinase-associated protein peptide<br />
[[1q3o]], [[1q3p]] - Crystal structure of the Shank PDZ-ligand complex <br/>
[[3l4f]] - rSHK1 PDZ domain + guanine nucleotide exchange factor 7 C terminal<br />
[[3qjm]], [[3qjn]] - rSHK1 PDZ domain + β-PIX<br />
[[3o5n]] - rSHK1 PDZ domain + inhibitor<br />
[[5o99]] – rSHK2 SH3 domain <br />
[[6cpj]] – rSHK2 SH3 domain - NMR<br />
[[2f3n]], [[2f44]] – rSHK3 SAM domain (mutant)<br />
[[5g4x]] – rSHK3 N-terminal<br />
[[5ova]] – rSHK3 PDZ domain <br />
[[5ovc]], [[5ovp]], [[5ovv]], [[6exj]] – rSHK3 PDZ domain + peptide<br />
[[5izu]] – SHK3 residues 533-655 + SAPAP3 peptide - mouse<br />
[[6kyk]] – mSHK3 NTD-ANK domain (mutant) + RAP1 <br />
[[6kyh]] – mSHK3 NTD-ANK domain (mutant) + HRas <br />


==References==
==References==
</StructureSection>
<references/>
<references/>
[[Category:Topic Page]]

Latest revision as of 11:38, 12 August 2024

      Shank (SH3 and multiple ankyrin repeat domains protein) Family Proteins are scaffolding proteins found in the postsynaptic density (PSD) of excitatory synapses. The PSD, a structure within the postsynaptic membrane of dendritic spines, contains a complex assembly of proteins which organize neurotransmitter receptors and regulatory elements.[1] The PSD coordinates communication of incoming signals to various targets and changes its composition in response to neural signals to aid neuronal plasticity[2] Shank proteins function as the master organizer of the PSD with 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, roughly 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] Shank also mediates the maturation of dendritic spines in neurons.[3] See also Neurodevelopmental Disorders.

  • SHANK1 mutations were detected in individuals with autism spectrum disorders[5].
  • SHANK2 is located at the postsynaptic membrane of glutamatergic neurons[6].
  • SHANK3 is enriched at the postsynaptic density of excitatory synapses[7].

Chromosome 22q13 Deletion Syndrome

     Chromosome 22q13 deletion syndrome (22q13DS) is a neurobehavioral syndrome marked by 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 cause the neurodevelopmental symptoms associated with 22q13DS, accounting for 1% of all autism cases.[8] At the molecular level, disruption of the full length Shank-3 protein reduces AMPA receptor signaling and spine remodeling.[4]Mice who were haploinsufficient for Shank-3, emitted fewer ultrasonic vocalizations during interactions with estrus female mice, a behavior reminiscent of that seen in Autism patients. Further, Shank knockout mice have less dendritic spine development, a diminished PSD size, decreased levels of proteins GKAP and Homer, and greatly impaired synaptic signaling. 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 aberrant levels of miRNAs for genes involved in ASDs like MeCP2, the cause of Rett Syndrome, NRXN-1, a gene implicated in ASDs, and Shank-3, adding support to Shank-3’s role in autism.[9] Due to the marked reduction in AMPA receptor signalling in Shank-3 mutants, compounds that enhance AMPA transmission (AMPAkinses) serve as potential therapeutic approaches to treating some ASDs.[4]

βPIX Structure

     βPIX is a protein belonging to a group of guanine nucleotide exchange factors used by Rho GTPase family members, like Rac1 and Cdc42. Rac1 and Cdc42 regulate the actin cytoskeleton of synapses.[10] 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.[10] The interaction of Shank with βPIX promotes the synaptic localization of βPIX and βPIX associated p21 Associated Kinase (PAK). Since PAK regulates actin cytoskeletons, and dendritic spines are actin-rich structures, it is believed that Shank recruits βPIX to dendritic 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.[10] 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.[10]

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 create the underlying structure of the PSD.[2] The of Shank-3 can () 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] It resembles the structure of a peg board, with Shank oligomers forming the board and PIX proteins forming the pegs to which things attach. 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.



Page Development

This article was developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University.

3D structures of Shank Family Proteins

Updated on 29-May-2025

6cpi – hSHK1 SH3 domain – human - NMR

1q3o – rSHK1 PDZ domain – rat
1q3p – rSHK1 PDZ domain + guanylate kinase-associated protein peptide
3l4f - rSHK1 PDZ domain + guanine nucleotide exchange factor 7 C terminal
3qjm, 3qjn - rSHK1 PDZ domain + β-PIX
3o5n - rSHK1 PDZ domain + inhibitor
5o99 – rSHK2 SH3 domain
6cpj – rSHK2 SH3 domain - NMR
2f3n, 2f44 – rSHK3 SAM domain (mutant)
5g4x – rSHK3 N-terminal
5ova – rSHK3 PDZ domain
5ovc, 5ovp, 5ovv, 6exj – rSHK3 PDZ domain + peptide
5izu – SHK3 residues 533-655 + SAPAP3 peptide - mouse
6kyk – mSHK3 NTD-ANK domain (mutant) + RAP1
6kyh – mSHK3 NTD-ANK domain (mutant) + HRas

References

Structure of rat Shank1 protein PDZ domain trimer complex with guanine nucleotide exchange factor 7 C terminal (yellow), 3l4f

Drag the structure with the mouse to rotate
  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. ↑ Gong X, Wang H. SHANK1 and autism spectrum disorders. Sci China Life Sci. 2015 Oct;58(10):985-90. PMID:26335738 doi:10.1007/s11427-015-4892-6
  6. ↑ Caumes R, Smol T, Thuillier C, Balerdi M, Lestienne-Roche C, Manouvrier-Hanu S, Ghoumid J. Phenotypic spectrum of SHANK2-related neurodevelopmental disorder. Eur J Med Genet. 2020 Dec;63(12):104072. PMID:32987185 doi:10.1016/j.ejmg.2020.104072
  7. ↑ Uchino S, Waga C. SHANK3 as an autism spectrum disorder-associated gene. Brain Dev. 2013 Feb;35(2):106-10. PMID:22749736 doi:10.1016/j.braindev.2012.05.013
  8. ↑ 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
  9. ↑ 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
  10. ↑ 10.0 10.1 10.2 10.3 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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