A topological and conformational stability alphabet for multipass membrane proteins

Area of Science:

• Structural biology
• Biochemistry
• Bioinformatics

Background:

• Multipass membrane proteins are crucial for cellular functions like signal transduction and transport.
• Understanding how their transmembrane helix (TMH) sequences dictate structure and flexibility is a significant challenge.

Purpose of the Study:

• To analyze sequence-structure relationships in interacting TMHs of membrane proteins.
• To identify universal principles governing membrane protein structure and dynamics.

Main Methods:

• Comprehensive analysis of membrane protein structures from the Protein Data Bank (PDB).
• Deconstruction of proteins into interacting TMH trimer units.
• Identification of recurrent sequence motifs and their correlation with topology and conformation.

Main Results:

• Membrane proteins can be classified into six distinct structural classes based on interacting TMH trimers.
• Recurrent sequence motifs associated with stabilizing interhelical contacts were identified.
• Protein topology and conformational flexibility were accurately predicted from these motifs.

Conclusions:

• Universal sequence-structure principles govern multipass membrane protein anatomy and plasticity.
• These findings can guide de novo structure prediction, protein design, and studies of folding and dynamics.