Shank protein: Difference between revisions

<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]]&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"/>

&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"/>

&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;The **canonical PDZ domain** contains 90 amino acids and folds into a compact **globular structure** consisting of a six-stranded β-sandwich flanked by two alpha helices.<ref name="IM"/> βPIX forms a **parallel trimer** via **helical interactions** within its CC domain, and with a **PDZ binding domain** at the C-terminus. Interestingly, only 1 Shank molecule is bound to the CC domain trimer of βPIX 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 βPIX 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 βPIX, tightly binding Glutamate -3. 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/2'>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.

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