Crystal structure of a disulfide-linked "trefoil" motif found in a large family of putative growth factors.
Porcine pancreatic spasmolytic polypeptide (PSP) belongs to a large family of homologous growth factor-like polypeptides characterized by a disulfide-linked "trefoil motif," duplicated and conserved in various family members. PSP contains two trefoil motifs, has several pharmacological actions on the gut, and has growth factor properties on epithelial cells in vitro. The human PSP analogue, human spasmolytic polypeptide, appears to be involved in many regenerative situations and, especially, in healing gastrointestinal ulcers. One member of the trefoil family, pS2, is secreted in approximately 50% of estrogen-dependent human breast carcinomas, which has led to its use as a tumor prognostic marker. Both pS2 and human spasmolytic polypeptide are also widely expressed in chronic gastrointestinal ulcerative conditions such as Crohn disease. Here we report the three-dimensional structure at 2.6-A resolution of a trefoil-containing protein, namely PSP, purified from porcine pancreas. The structure shows two homologous domains that share a supersecondary structure and disulfide bond pattern. The two domains pack asymmetrically giving rise to a number of protruding loops, exposed clefts, and an unusual electrostatic surface potential. Knowledge of the structure of PSP should allow the design of mutants to investigate further the function of PSP and other trefoil-containing peptides.
De
A
A
Protein Structure Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
Brown
D G
DG
Gorman
M A
MA
Carr
M
M
Sanderson
M R
MR
Freemont
P S
PS
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004563:Electrochemistry; D006133:Growth Substances / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010179:Pancreas / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013552:Swine; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3
D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; C099037:TFF3 protein, rat; C000604008:Tff2 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; C034407:pancreatic spasmolytic polypeptide