Influence of proline residues in transmembrane helix packing.
Integral membrane proteins often contain proline residues in their alpha-helical transmembrane (TM) fragments, which may strongly influence their folding and association. Pro-scanning mutagenesis of the helical domain of glycophorin A (GpA) showed that replacement of the residues located at the center abrogates helix packing while substitution of the residues forming the ending helical turns allows dimer formation. Synthetic TM peptides revealed that a point mutation of one of the residues of the dimerization motif (L75P) located at the N-terminal helical turn of the GpA TM fragment, adopts a secondary structure and oligomeric state similar to the wild-type sequence in detergents. In addition, both glycosylation mapping in biological membranes and molecular dynamics showed that the presence of a proline residue at the lipid/water interface has as an effect the extension of the helical end. Thus, helix packing can be an important factor that determines appearance of proline in TM helices. Membrane proteins might accumulate proline residues at the two ends of their TM segments in order to modulate the exposition of key amino acid residues at the interface for molecular recognition events while allowing stable association and native folding.
Orzáez
Mar
M
Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46 100 Burjassot, Spain.
Salgado
Jesús
J
Giménez-Giner
Ana
A
Pérez-Payá
Enrique
E
Mingarro
Ismael
I
D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D039301:Computers, Molecular; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D006021:Glycophorins / Q000737:chemistry* / Q000378:metabolism*; D006031:Glycosylation; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000378:metabolism; D011392:Proline / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry
D006021:Glycophorins; D008055:Lipids; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014867:Water; D011392:Proline