Structural Basis for the Immunogenic Properties of the Meningococcal Vaccine Candidate LP2086.
LP2086 is a family of outer membrane lipoproteins from Neisseria meningitidis, which elicits bactericidal antibodies and are currently undergoing human clinical trials in a bivalent formulation where each antigen represents one of the two known LP2086 subfamilies. Here we report the NMR structure of the recombinant LP2086 variant B01, a representative of the LP2086 subfamily B. The structure reveals a novel fold composed of two domains: a "taco-shaped" N-terminal beta-sheet and a C-terminal beta-barrel connected by a linker. The structure in micellar solution is consistent with a model of LP2086 anchored to the outer membrane bilayer through its lipidated N terminus. A long flexible chain connects the folded part of the protein to the lipid anchor and acts as spacer, making both domains accessible to the host immune system. Antibodies broadly reactive against members from both subfamilies have been mapped to the N terminus. A surface of subfamily-defining residues was identified on one face of the protein, offering an explanation for the induction of subfamily-specific bactericidal antibodies.
Mascioni
Alessandro
A
Wyeth Research, Structural Biology and Computational Chemistry, Cambridge, Massachusetts 02140 and Wyeth Vaccines Research, Pearl River, New York 10965, USA.
Bentley
Breagh E
BE
Camarda
Rosaria
R
Dilts
Deborah A
DA
Fink
Pamela
P
Gusarova
Viktoria
V
Hoiseth
Susan K
SK
Jacob
Jaison
J
Lin
Shuo L
SL
Malakian
Karl
K
McNeil
Lisa K
LK
Mininni
Terri
T
Moy
Franklin
F
Murphy
Ellen
E
Novikova
Elena
E
Sigethy
Scott
S
Wen
Yingxia
Y
Zlotnick
Gary W
GW
Tsao
Désirée H H
DH
D000818:Animals; D000907:Antibodies, Bacterial / Q000737:chemistry* / Q000276:immunology; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000276:immunology; D022401:Meningococcal Vaccines / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008823:Micelles; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D010449:Peptide Mapping / Q000379:methods; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D008051:Lipid Bilayers; D022401:Meningococcal Vaccines; D008823:Micelles; D011994:Recombinant Proteins; C484699:factor H-binding protein, Neisseria meningitidis