NMR structure in a membrane environment reveals putative amyloidogenic regions of the SEVI precursor peptide PAP(248-286).
Semen is the main vector for HIV transmission worldwide. Recently, a peptide fragment (PAP(248-286)) has been isolated from seminal fluid that dramatically enhances HIV infectivity by up to 4-5 orders of magnitude. PAP(248-286) appears to enhance HIV infection by forming amyloid fibers known as SEVI, which are believed to enhance the attachment of the virus by bridging interactions between virion and host-cell membranes. We have solved the atomic-level resolution structure of the SEVI precursor PAP(248-286) using NMR spectroscopy in SDS micelles, which serve as a model membrane system. PAP(248-286), which does not disrupt membranes like most amyloid proteins, binds superficially to the surface of the micelle, in contrast to other membrane-disruptive amyloid peptides that generally penetrate into the core of the membrane. The structure of PAP(248-286) is unlike most amyloid peptides in that PAP(248-286) is mostly disordered when bound to the surface of the micelle, as opposed to the alpha-helical structures typically found of most amyloid proteins. The highly disordered nature of the SEVI peptide may explain the unique ability of SEVI amyloid fibers to enhance HIV infection as partially disordered amyloid fibers will have a greater capture radius for the virus than compact amyloid fibers. Two regions of nascent structure (an alpha-helix from V262-H270 and a dynamic alpha/3(10) helix from S279-L283) match the prediction of highly amyloidogenic sequences and may serve as nuclei for aggregation and amyloid fibril formation. The structure presented here can be used for the rational design of mutagenesis studies on SEVI amyloid formation and viral infection enhancement.
Nanga
Ravi P R
RP
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Brender
Jeffrey R
JR
Vivekanandan
Subramanian
S
Popovych
Nataliya
N
Ramamoorthy
Ayyalusamy
A
D000682:Amyloid / Q000737:chemistry*; D015658:HIV Infections / Q000821:virology; D009682:Magnetic Resonance Spectroscopy; D008567:Membranes, Artificial; D010446:Peptide Fragments / Q000737:chemistry*; D012661:Semen / Q000737:chemistry* / Q000821:virology
D000682:Amyloid; D008567:Membranes, Artificial; D010446:Peptide Fragments