Dissecting membrane protein architecture: An annotation of structural complexity

Abstract

alpha-Helical membrane proteins exist in an anisotropic environment which strongly influences their folding, stability, and architecture, which is far more complex than a simple bundle of transmembrane helices, notably due to helix deformations, prosthetic groups and extramembrane structures. However, the role and the distribution of such heterogeneity in the supra molecular organization of membrane proteins remains poorly investigated. Using a nonredundant subset of alpha-helical membrane proteins, we have annotated and analyze the statistics of several types of new elements such as incomplete helices, intramembrane loops, helical extensions of helical transmembrane domains, extracellular loops, and helices lying parallel to the membrane surface. The relevance of the annotation scheme was studied using residue composition, statistics, physical chemistry, and symmetry of their distribution in relation to the immediate membrane environment. Calculation of hydrophobicity using different scales show that different structural elements appear to have affinities coherent with their position in the membrane. Examination of the annotation scheme suggests that there is considerable information content in the amino acid compositions of the different elements suggesting that it might be useful for structural prediction. More importantly, the proposed annotation will help to decipher the complex hierarchy of interactions involved in membrane protein architecture.

Antenna mixing in photosynthetic membranes from Phaeospirillum molischianum

“…We believe that these observations can probably be generalized. Many membrane proteins are oligomers of one or several polypeptides (37), and frequently these polypeptides are members of closely related multigene families. The presence of such heterogenity will be a challenge for structural biology where ensemble techniques, such as crystallography or NMR, deal poorly with a stochastically mixed sample.…”

Single-spanning transmembrane domains in cell growth and cell-cell interactions

“…This is due to several interlinked reasons: the difficulties to solubilize and purify these hydrophobic proteins, the disordered nature of their lipid environment and the complex nature of many membrane proteins which are oligomers of one or several polypeptides. 30,66 One major consequence of these technical hurdles is the under-representation of membrane protein structures in the PDB database. At the end of 2008 and 2009, only 180 and 217 respectively, unique structures of membrane proteins were available (http://blanco.biomol.…”

“…drorlist.com/nmr/MPNMR.html). 30 Only seven structures of dimers of TM helices, to date, have been deposited in the PDB. Properties fo the structures are summarized in Table 1.…”

“…Many aspects of this topic have recently been reviewed in excellent papers. 7,11,12,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] A brief summary of current knowledge, obtained through biophysical, biochemical, cell biological and genetic studies can be put forward:…”

“…Polar residues are rare, especially negatively charged ones, whereas singlespanning segments are more hydrophobic than multi-spanning helices. 30,42 (2) Analysis of polytopic membrane structures and studies on model or natural single TM peptides has provided many insights on packing "rules" for TM helices. Sequence and geometric motifs have been found to drive these interactions, in a similar way as small modular domains (such as leucine zippers) that mediate soluble proteins interactions.…”