Structure-activity analysis of histatin, a potent wound healing peptide from human saliva: cyclization of histatin potentiates molar activity 1,000-fold.
Wounds in the mouth heal faster and with less scarification and inflammation than those in the skin. Saliva is thought to be essential for the superior oral wound healing, but the involved mechanism is still unclear. We have previously discovered that a human-specific peptide, histatin, might be implicated in the wound-healing properties of saliva. Here we report that histatin enhances reepithelialization in a human full-skin wound model closely resembling normal skin. The peptide does not stimulate proliferation but induces cell spreading and migration, two key initiating steps in reepithelialization. Activation of cells by histatin requires a G-protein-coupled receptor that activates the ERK1/2 pathway. Using a stepwise-truncation method, we determined the minimal domain (SHREFPFYGDYGS) of the 38-mer-parent peptide that is required for activity. Strikingly, N- to C-terminal cyclization of histatin-1 potentiates the molar activity approximately 1000-fold, indicating that the recognition of histatin by its cognate receptor requires a specific spatial conformation of the peptide. Our results emphasize the importance of histatin in human saliva for tissue protection and recovery and establish the experimental basis for the development of synthetic histatins as novel skin wound-healing agents.
Oudhoff
Menno J
MJ
Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. mj.oudhoff@vumc.nl
Kroeze
Kim L
KL
Nazmi
Kamran
K
van den Keijbus
Petra A M
PA
van 't Hof
Wim
W
Fernandez-Borja
Mar
M
Hordijk
Peter L
PL
Gibbs
Susan
S
Bolscher
Jan G M
JG
Veerman
Enno C I
EC
D000595:Amino Acid Sequence; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003500:Cyclization; D004357:Drug Synergism; D054808:Histatins / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D008954:Models, Biological; D012463:Saliva / Q000737:chemistry; D013329:Structure-Activity Relationship; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D054808:Histatins