Hepcidin revisited, disulfide connectivity, dynamics, and structure.
Hepcidin is a tightly folded 25-residue peptide hormone containing four disulfide bonds, which has been shown to act as the principal regulator of iron homeostasis in vertebrates. We used multiple techniques to demonstrate a disulfide bonding pattern for hepcidin different from that previously published. All techniques confirmed the following disulfide bond connectivity: Cys(1)-Cys(8), Cys(3)-Cys(6), Cys(2)-Cys(4), and Cys(5)-Cys(7). NMR studies reveal a new model for hepcidin that, at ambient temperatures, interconverts between two different conformations, which could be individually resolved by temperature variation. Using these methods, the solution structure of hepcidin was determined at 325 and 253 K in supercooled water. X-ray analysis of a co-crystal with Fab appeared to stabilize a hepcidin conformation similar to the high temperature NMR structure.
Jordan
John B
JB
Department of Molecular Structure, Amgen, Inc., Thousand Oaks, California 91320, USA. jbjordan@amgen.com
Poppe
Leszek
L
Haniu
Mitsuru
M
Arvedson
Tara
T
Syed
Rashid
R
Li
Vivian
V
Kohno
Hiko
H
Kim
Helen
H
Schnier
Paul D
PD
Harvey
Timothy S
TS
Miranda
Les P
LP
Cheetham
Janet
J
Sasu
Barbra J
BJ
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000502:physiology
D023181:Antimicrobial Cationic Peptides; D004220:Disulfides; C578702:HAMP protein, human; D064451:Hepcidins