Identification of Multi-Residue Motifs in Short Sequence Fragments of Membrane Protein

Abstract

University of Illinois at Chicago, Chicago, IL, USA.Membrane proteins are abundant in most species and have diverse biological functions that include signal transduction, proton pumping, cell trafficking and photosynthesis. Understanding their structural organization and the principles governing their folding and assembly is an important task. Probabilistic models have been developed to identify sequence motifs consist of residue pairs in transmembrane (TM) regions of membrane proteins. Motifs such as GG4 in alpha-helical membrane proteins and AY2 in beta-barrel membrane proteins are well recognized. However, it is not clear whether motifs exist in loop regions of membrane proteins and whether multi-residue (>2) motifs play roles in membrane protein structural assembly. Using a combinatorial and statistical model, we have analyzed both TM regions and loop regions of a set of 41 non-homologous alpha-helical proteins and 25 non-homologous beta-barrel proteins with known structures. We have discovered several significant motifs, (V/I/L)x(V/I/L)x(A/G) along with five others occurs in approximately 70% of the beta-strands. These six motifs can be regarded as the building blocks of beta-barrel membrane proteins. We have also identified several additional motifs including YxRxG that likely help in membrane fusion and binding to transport factors such as the skp chaperone. Based on these results, several experimentally testable hypotheses have emerged that can help to understand the folding pathway of membrane proteins.