Shank protein: Difference between revisions

<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 (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]].

&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.

 

==3D structures of Shank Family Proteins==

 

 

[[3qjm]], [[3qjn]] - rSHK1 PDZ domain + β-PIX<br />

[[3o5n]] - rSHK1 PDZ domain + inhibitor<br />

[[6cpj]] – rSHK2 SH3 domain - NMR<br />

[[2f3n]], [[2f44]] – rSHK3 SAM domain (mutant)<br />

[[5g4x]] – rSHK3 N-terminal<br />

[[5ovc]], [[5ovp]], [[5ovv]], [[6exj]] – rSHK3 PDZ domain + peptide<br />

[[6kyk]] – mSHK3 NTD-ANK domain (mutant) + RAP1 <br />

[[6kyh]] – mSHK3 NTD-ANK domain (mutant) + HRas <br />