Mutations in transmembrane proteins: diseases, evolutionary insights, prediction and comparison with globular proteins

Abstract

Membrane proteins are unique in that they interact with lipid bilayers, making them indispensable for transporting molecules and relaying signals between and across cells. Due to the significance of the protein’s functions, mutations often have profound effects on the fitness of the host. This is apparent both from experimental studies, which implicated numerous missense variants in diseases, as well as from evolutionary signals that allow elucidating the physicochemical constraints that intermembrane and aqueous environments bring. In this review, we report on the current state of knowledge acquired on missense variants (referred to as to single amino acid variants) affecting membrane proteins as well as the insights that can be extrapolated from data already available. This includes an overview of the annotations for membrane protein variants that have been collated within databases dedicated to the topic, bioinformatics approaches that leverage evolutionary information in order to shed light on previously uncharacterized membrane protein structures or interaction interfaces, tools for predicting the effects of mutations tailored specifically towards the characteristics of membrane proteins as well as two clinically relevant case studies explaining the implications of mutated membrane proteins in cancer and cardiomyopathy.

Interpreting the molecular mechanisms of disease variants in human transmembrane proteins

“…1E, Table 1). While we cannot exclude that this enrichment is in part due to an increased focus on the transmembrane region in clinical research, we suggest—in line with previous work (63, 64)—that this observation also reflects a decreased mutational tolerance of the transmembrane region.…”

Loss of altruism in the social amoebaDictyostelium discoideumis associated with the G protein-coupled receptorgrlG

“…From the great deal of work with GPCRs in humans and disease in particular, it is clear that mutations in membrane proteins can result in a huge variety of impacts. The effect of any mutation will depend on the properties of the protein as well as the type and location of the mutation (Schöneberg and Liebscher 2021; Zaucha et al . 2021).…”

“…From the great deal of work with GPCRs in humans and disease in particular, it is clear that mutations in membrane proteins can result in a huge variety of impacts. The effect of any mutation will depend on the properties of the protein as well as the type and location of the mutation (Schöneberg and Liebscher 2021;Zaucha et al 2021). Some of the many potential impacts of GPCR mutations include improper membrane trafficking or localization; alterations to critical secondary or tertiary structures; inhibition or altered efficiency of binding ligand(s) or interacting proteins and inhibition or altered efficiency of signaling through downstream effectors.…”

TMEM135 is a Novel Regulator of Mitochondrial Dynamics and Physiology with Implications for Human Health Conditions

“…A number of transmembrane transporters couple the inward movement of one solute to the outward movement of another [ 11 ]. Misfolding of transmembrane transporters is associated with a variety of clinical conditions [ 1 , 2 , 12 , 13 ].…”