Protein Structure in Membrane Domains

Abstract

Of great interest to the academic and pharmaceutical research communities, helical transmembrane proteins are characterized by their ability to dissolve and fold in lipid bilayers-properties conferred by polypeptide spans termed transmembrane domains (TMDs). The apolar nature of TMDs necessitates the use of membrane-mimetic solvents for many structure and folding studies. This review examines the relationship between TMD structure and solvent environment, focusing on principles elucidated largely in membrane-mimetic environments with single-TMD protein and peptide models. Following a brief description of TMD sequence and conformational characteristics gleaned from the structural database, we present an overview of the conceptual models used to study folding in vitro. The impact of sequence and solvent context on the incorporation of TMDs into membranes, and its role in measurements of TMD self-assembly strengths, is then described. We conclude with a discussion of the nonspecific effects of membrane components on TMD stability. 135 Annu. Rev. Biophys. 2012.41:135-155. Downloaded from www.annualreviews.org by Indiana University -Purdue University Indianapolis -IUPUI on 10/01/12. For personal use only.

Thermodynamic and kinetic characterization of transmembrane helix association

“…1,9 Non-specific contributions that could play an important role are only now being recognized as important and further studies are required to quantify their effect. 1 Although the bilayer has been previously implicated as an important factor in transmembrane helix dimerization, 30,31 our current study provides a direct quantitative estimate of the lipid contributions in the absence of sequence motifs. Furthermore, our calculations reveal favorable backbone-backbone interactions that together with the lipid effects act as a generic driving force of transmembrane helix association.…”

“…[1][2][3] Interestingly, several helical membrane proteins require a stable or transient association for their function, and recent evidence points to a ligand-independent association kinetics. 4,5 High resolution microscopy methods have revealed new insights into monomer-dimer equilibrium within membranes, 6 but the link between the molecular interactions and the population behavior is still missing.…”

Effect of Lipid Bilayer Composition on Membrane Protein Association

“…Membrane proteins play important roles in several cellular processes and are involved in pathological mechanisms underlying various human diseases [8]. These proteins interact and associate with one another to form large multimers, several of which have physiological roles [9].…”

“…Several approaches have been successful in predicting the structure of transmembrane dimers, but higher order oligomers have been less tractable [8]. Continuum methods with an implicit membrane model coupled with a scoring function have been used to analyze the associated state of transmembrane helices [44].…”

Polar Residues and Their Positional Context Dictate the Transmembrane Domain Interactions of Influenza A Neuraminidases

“…In both cases, the TMDs can be involved in a range of crucial functions from protein topology and trafficking, to assembly, transport across the membrane, signal transduction, and energy production. To acquire these functions, newly synthesized TMDs must first partition to the membrane where they can fold, insert, and make lateral interactions (3)(4)(5)(6). Currently, how TMDs from bitopic proteins fold and interact laterally is less characterized than in multispanning transmembrane proteins.…”