Shank protein: Difference between revisions
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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 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"/> | ||
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/ | 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/3'>11 Angstrom displacement</scene> to make room for the βPIX PDZ binding domain.<ref name="IM"/> | ||
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 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. | ||