In silico genome and 3D protein structure analyses of FAM72

Abstract

FAM72 is a novel neuronal progenitor cell (NPC) self-renewal supporting protein expressed under physiological conditions at low levels in other tissues. Accumulating data indicate the potential pivotal tumorigenic effects of the FAM72 gene family. My in silico human genome-wide analysis (GWA) revealed that the FAM72 gene family consists of four human-specific paralogous members, all of which are located on chromosome (chr) 1. Unique asymmetric FAM72 segmental gene duplications are most likely to have occurred in conjunction with the paired genomic neighbor SRGAP2 (SLIT-ROBO Rho GTPase activating protein), as both genes have four paralogues in humans but only one vertebra-emerging orthologue in all other species. No species with two or three FAM72/SRGAP2 gene pairs could be identified, and the four exclusively human-defining ohnologues, with different mutation patterns in Homo neanderthalensis and Denisova hominin, may remain under epigenetic control through long non-coding (lnc) RNAs. Due to the pivotal role in tumorigenesis, I determined the three-dimensional (3D) protein structure of human FAM72A using state of the art in silico physicochemical analyses (e.g., I-TASSER, RaptorX, and Modeller) and further identified potential ligand-protein interactions. My data indicate a Zn2+/Fe3+-containing 3D protein structure, based on a 3GA3_A model template, which potentially interacts with the organic molecule RSM ((2s)-2-(acetylamino)-Nmethyl-4-[(R)-methylsulfinyl] butanamide). The discovery of RSM may serve as potential lead for further anti-FAM72A drug screening tests in the pharmaceutical industry because interference with FAM72A’s activities via RSM-related molecules might be a novel option for the treatment of various types of cancers.|FAM72는 신경전구세포(NPC)의 증식에 관여하는 것으로 알려진 새로운 단백질이며, 신경조직 이외 다른 조직에서는 발현 정도가 낮음. 최근 발표된 연구결과들은 FAM72 유전자 군이 발암 가능성을 가진 것으로 보고함. In silico human genome-wide analysis (GWA)를 통해 FAM72 유전자 군은 4개의 인간-특이적 유사유전자로 구성되어 있음을 알 수 있었고, 이들은 모두 1번 염색체상에 위치함. FAM72 특유의 비대칭 유전자 쌍(asymmetric segmental gene duplication)은 SRGAP2 (SLIT-ROBO Rho GTPase activating protein) 유전자와 함께 쌍을 이루는 형태로 구성됨. 이 두 유전자는 인체에서는 4 가지의 paralogous 유전자형을 가지지만 다른 모든 종에서는 오직 하나의 orthologous 유전자형을 보임. FAM72/SRGAP2 유전자가 2가지 또는 3가지의 쌍을 이루는 종에 대해서는 보고된 적이 없으며, 인간에서만 독점적으로 나타나는 4개의 ohnologues 유전자형은 Homo neanderthalensis and Denisova hominin의 다른 돌연변이 형질과 함께, long non-coding (lnc) RNAs에 의해 후성유전학적으로 (epigenetically) 조절되는 것으로 여겨짐. 종양형성과의 연관성을 알아보기 위해, 최신 기법인 in silico physicochemical analyses (e.g., I-TASSER, RaptorX, and Modeller)를 활용하여 인간 FAM72 단백질의 3차원 구조를 밝히고, 이와 결합가능성을 가진 단백질들을 알아냄. GA3_A model 템플릿을 기반으로 한 Zn2+/Fe3+-containing 3차원 단백질 구조는 유기분자인 RSM ((2s)-2-(acetylamino)-Nmethyl-4-[(R)-methylsulfinyl] butanamide) 과 상호작용 할 것으로 예상됨. FAM72 결합요소인 RSM의 발견은 향후 제약산업에서 항 FAM72 제재의 발굴에 활용 될 수 있음. RSM 관련 분자를 이용한 FAM72A 단백질의 활성 저해는 다양한 형질의 암을 치료하는 새로운 선택지가 될 것임.; FAM72 is a novel neuronal progenitor cell (NPC) self-renewal supporting protein expressed under physiological conditions at low levels in other tissues. Accumulating data indicate the potential pivotal tumorigenic effects of the FAM72 gene family. My in silico human genome-wide analysis (GWA) revealed that the FAM72 gene family consists of four human-specific paralogous members, all of which are located on chromosome (chr) 1. Unique asymmetric FAM72 segmental gene duplications are most likely to have occurred in conjunction with the paired genomic neighbor SRGAP2 (SLIT-ROBO Rho GTPase activating protein), as both genes have four paralogues in humans but only one vertebra-emerging orthologue in all other species. No species with two or three FAM72/SRGAP2 gene pairs could be identified, and the four exclusively human-defining ohnologues, with different mutation patterns in Homo neanderthalensis and Denisova hominin, may remain under epigenetic control through long non-coding (lnc) RNAs. Due to the pivotal role in tumorigenesis, I determined the three-dimensional (3D) protein structure of human FAM72A using state of the art in silico physicochemical analyses (e.g., I-TASSER, RaptorX, and Modeller) and further identified potential ligand-protein interactions. My data indicate a Zn2+/Fe3+-containing 3D protein structure, based on a 3GA3_A model template, which potentially interacts with the organic molecule RSM ((2s)-2-(acetylamino)-Nmethyl-4-[(R)-methylsulfinyl] butanamide). The discovery of RSM may serve as potential lead for further anti-FAM72A drug screening tests in the pharmaceutical industry because interference with FAM72A’s activities via RSM-related molecules might be a novel option for the treatment of various types of cancers.