engleski

Transmembrane Distribution of Alpha-Helix Preferences and Triplets of Positive Charges in Membrane Protein Sequences.

The amino acid sequence of integral membrane protein passes through a membrane at least once. The first goal of sequence analysis is to assign a sequence position for all transmembrane segments and IN (cytoplasmic) and OUT (extracytoplasmic) location for all extramembrane loops. These assignments define the transmembrane topology of a protein. The best known topological determinants for extramembrane loops are higher number of positive charges (Arg and Lys) in cytoplasmic loops (the positive inside rule), charge difference across first transmembrane segment, and asymmetry in the amino acid composition of outside and inside loops. In this work we present two novel classes of more specific topological determinants. The first calss can be regarded as the "folding inside rule", because it is an asymmetry in alpha-helix preferences favoring early helix formation near cytoplasmic ends of future transmembrane segments. Clusters of positive charges, containing at least three such charges close enough in the sequence, are also topological determinants. Charge triplets are found much more often in cytoplasmic than in extracytoplasmic loops, even after taking into account higher number of positive charges in cytoplasmic loops. This observation can be described as the "triplet inside bias" or "triplet inside rule". We show that whenever triplet bias is present in the sequence it is likely to increase the performance for topology prediction. On another hand, when positive charge bias, triplet charge bias and charge difference across first transmembrane segment are all absent in the sequence, "folding inside rule" can still be used to obtain the topology prediction. Our topology predictor combines triplet inside rule, positive inside rule, charge difference rule and folding inside rule. It predicts the N-terminus location with greater accuracy than positive inside rule and it can be used to uncover errors in proposed membrane protein topology and/or to select correct topological model.

membrane protein; topology; positive inside rule; charge triplets; helix preferences; transmembrane distribution; topological signals

nije evidentirano