Structural Evolution of Human-Specific SRGAP2 Proteins

Abstract

In the development of the human brain, human-specific genes are considered to play key roles, bringing about its unique advantages and vulnerabilities. At the time when the Homo lineage diverged from Australopithecus, SRGAP2C gradually emerged (3.4-2.4 million years ago, mya) through a process of serial duplications and mutagenesis from the ancestral SRGAP2A. Remarkably, ectopic expression of SRGAP2C endowed mouse brain cultured cells, with human-specific morphologies. To understand the molecular mechanisms underlying SRGAP2A and SRGAP2C function, we have determined the structure of SRGAP2A by an exhaustive molecular symmetry search, utilizing the conserved biological symmetry of the F-BAR fold, and studied the interplay between SRGAP2A and SRGAP2C. We found that: (i) SRGAP2A homo-dimerizes through a large interface that includes an F-BAR, a newly identified F-BAR extension (Fx), and RhoGAP-SH3 domains. (ii) SRGAP2A has an unusual inverse geometry, which enables it to associate with lamellipodia and dendritic spine heads in vivo, and to scaffold membrane protrusions in cell culture. (iii) As a result of the initial partial duplication event (∼3.4 mya), SRGAP2C carries a defective Fx-domain that severely compromises its solubility and membrane scaffolding. Consistently, SRGAP2A:SRAGP2C hetero-dimers are insoluble and therefore likely to be inactive. (iv) The level of SRGAP2A inactivation depends on its hetero-dimerization with SRGAP2C. We found that the primal form of SRGAP2C (P-SRGAP2C, existing between ∼3.4-2.4 mya) is less effective in hetero-dimerizing with SRGAP2A than the modern form of the protein, which carries several substitutions (∼2.4 mya). Thus, the adaptive mutagenesis phase contributed to SRGAP2C activity by improving its ability to associate with SRGAP2A, which indicates a stepwise involvement of SRGAP2C in human evolutionary history.To the best of our knowledge, this is a first detailed structural description of a human specific protein.