Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Poster Abstracts

41-POS Board 11 DISCOVERY OF VERY IMPORTANT MEMBRANE PROTEINS (VIMPS) THAT HAVE ESCAPED PREVIOUS ATTENTION Charles R. Sanders 1 ; Tucker L Apgar 1 ; Adam L Sanders 1 ; Jake Hermanson 1 ; 1 Vanderbilt University School of Medicine - Basic Sciences, Biochemistry, Nashville, TN, USA Bioinformatic studies were conducted to identify membrane proteins of great biological and/or biomedical relevance that have previously eluded notice as “very important membrane proteins” (VIMPs). Here we pursued two different approaches to generate a list of VIMPs that can be used, among other applications, by new investigators seeking to establish new projects involving membrane proteins of high significance. Our first approach was to explore Mendelian diseases and their causative proteins. “Simple” Mendelian diseases are genetic disorders that are caused by pathogenic mutations in a single gene. Although these disorders are considered promising drug targets due to their simple etiology, they typically are classified as rare disorders, which has historically discouraged drug discovery efforts to target that disease by the pharmaceutical industry. However, a number or these diseases are not that rare. Here we systematically explored the several thousand known Mendelian disorders and compiled as list of all those that have a prevalence or incidence of higher than 5.0 (1 in 20,000 people) and that are known to be caused by single gene mutations. We found that there are 74 such “common rare” disorders and compiled a list of the causative genes and their encoded proteins, some of which are understudied membrane proteins. In a second approach we also explored the entire human proteome by applying missense intolerance analysis to all possible 31 amino acid segments of all human proteins to determine whether each segment is intolerant to mutation in the gnomAD collection of human genes. For the roughly 20,000 human proteins it was found that 290 proteins are so important that they contain at least one 31 residue segment in which amino acid mutations are absolutely not seen in the >10 5 human gene sequences currently deposited in gnomAD. Such proteins are deemed to be subject to “purifying selection” by evolution. Of these zero-tolerance proteins, 37 were integral membrane proteins. While some of these proteins are well known, such as the ryanodine receptor, some have received almost no attention to date despite the fact that natural selection finds them to be VIMPs. It is hoped that the list of VIMPs generated here based both on analysis of Mendelian disorders and on genetic intolerance analysis will be useful to those investigators, especially new investigators, looking to establish projects that focus on a VIMP and its associated biology and disease relatedness.

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