Understanding transmembrane helix interaction on the structural level

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Understanding how transmembrane (TM) helices recognize each other is an important and challenging problem. Here I propose to utilize the integrin system to study structural and sequence determinants of TM helix interaction preferences. Integrins are a family of dimeric single-pass membrane proteins that act as cell adhesion receptors. Integrins are known to exist in at least two states - an active state, where they bind extracellular ligands and an inactive state, where this binding does not occur. It has been shown that peptides that interfere-with the dimerization of integrin TM helices, by interacting with one of the monomers, cause integrin activation. The ability to consistently design such peptides de novo critically depends on our understanding of TM helix interaction preferences. Therefore, to study these preferences, I will establish a cycle between the computational design of such peptides and their experimental characterization. I will design: 1) peptides that disrupt the TM helix association of alpha2beta1 and alpha4beta1 by interacting with the alpha subunits and 2) peptides that stabilize the TM helix association of alphallbbetaS by forming a trimeric helix bundle with the native dimer. I will also make use of the fact that integrins are a diverse family (with 18 alpha and 8 beta subunits known in vertebrates) to study the problem of designing TM helix interaction specificity. Integrins are involved in many biologically critical processes and are associated with such human conditions as cancer angiogenesis and metastasis and various bleeding disorders. By deciphering the principles of integrin TM interaction specificity, this work will suggest ways to selectively activate or deactivate particular receptors, which can lead to novel therapies. Additionally, understanding the determinants of TM helix interactions in general will have a wider impact on dissecting transmembrane protein folding and interaction. PUBLIC HEALTH RELEVANCE: Integrins are a family of proteins that that are involved in a great variety of biological processes and human diseases, from immune response and leukocyte trafficking to cancer, development and blot clotting. Central to the function of integrins is the association between their transmembrane (TM) regions. This work will shed light on the principles by which TM regions recognize each other, which will provide a way of controlling integrin activity and will likely lead to novel therapies.