5i6j
From Proteopedia
Crystal Structure of SRGAP2 F-BARx
Structural highlights
DiseaseSRGP2_HUMAN A chromosomal aberration disrupting SRGAP2 has been found in a patient with early infantile epileptic encephalopathy. Balanced translocation t(1;9)(q32;q13). FunctionSRGP2_HUMAN RAC1 GTPase activating protein (GAP) that binds and deforms membranes, and regulates actin dynamics to regulate cell migration and differentiation. Plays an important role in different aspects of neuronal morphogenesis and migration mainly during development of the cerebral cortex. This includes the biogenesis of neurites, where it is required for both axons and dendrites outgrowth, and the maturation of the dendritic spines. Also stimulates the branching of the leading process and negatively regulates neuron radial migration in the cerebral cortex. Its interaction and inhibition by SRGAP2C reduces the rate of spine maturation, alters dendritic spine morphology and density and indirectly increases neuronal migration. It may have implications for cognition, learning and memory. In non-neuronal cells, it may also play a role in cell migration by regulating the formation of lamellipodia and filopodia.[1] [2] [3] Publication Abstract from PubMedIn the development of the human brain, human-specific genes are considered to play key roles, conferring its unique advantages and vulnerabilities. At the time of Homo lineage divergence from Australopithecus, SRGAP2C gradually emerged through a process of serial duplications and mutagenesis from ancestral SRGAP2A (3.4-2.4 Ma). Remarkably, ectopic expression of SRGAP2C endows cultured mouse brain cells, with human-like characteristics, specifically, increased dendritic spine length and density. To understand the molecular mechanisms underlying this change in neuronal morphology, we determined the structure of SRGAP2A and studied the interplay between SRGAP2A and SRGAP2C. We found that: 1) SRGAP2A homo-dimerizes through a large interface that includes an F-BAR domain, a newly identified F-BAR extension (Fx), and RhoGAP-SH3 domains. 2) SRGAP2A has an unusual inverse geometry, enabling associations with lamellipodia and dendritic spine heads in vivo, and scaffolding of membrane protrusions in cell culture. 3) As a result of the initial partial duplication event ( approximately 3.4 Ma), SRGAP2C carries a defective Fx-domain that severely compromises its solubility and membrane-scaffolding ability. Consistently, SRGAP2A:SRAGP2C hetero-dimers form, but are insoluble, inhibiting SRGAP2A activity. 4) Inactivation of SRGAP2A is sensitive to the level of hetero-dimerization with SRGAP2C. 5) The primal form of SRGAP2C (P-SRGAP2C, existing between approximately 3.4 and 2.4 Ma) is less effective in hetero-dimerizing with SRGAP2A than the modern SRGAP2C, which carries several substitutions (from approximately 2.4 Ma). Thus, the genetic mutagenesis phase contributed to modulation of SRGAP2A's inhibition of neuronal expansion, by introducing and improving the formation of inactive SRGAP2A:SRGAP2C hetero-dimers, indicating a stepwise involvement of SRGAP2C in human evolutionary history. Structural History of Human SRGAP2 Proteins.,Sporny M, Guez-Haddad J, Kreusch A, Shakartzi S, Neznansky A, Cross A, Isupov MN, Qualmann B, Kessels MM, Opatowsky Y Mol Biol Evol. 2017 Feb 21. doi: 10.1093/molbev/msx094. PMID:28333212[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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