RGD SEQUENCES IN SEVERAL RECEPTOR PROTEINS - NOVEL CELL-ADHESION FUNCTION OF RECEPTORS

In the process of homology modelling of the 3-dimensional structure of alleles of the human histocompatibility protein HLA-DQ, we discovered that its RGD tripeptide (beta 167-169) forms part of a loop. A search through protein sequence data bases, revealed this cell adhesion moti f in 67 integral plasma membrane proteins (in 48 extracellularly, and in the remaining 19 intracellularly), which are bona fide receptors, a nd none of them has thus far been considered as a cell adhesion protei n. The 3-dimensional structure of one of these, the rat neonatal F-c r eceptor, is known and its extracellular RGD sequence is in an adhesion -like loop, a fact that went unnoticed in the original papers. In a fe w other cases, e.g. rat and mouse growth hormone receptor, and mouse C D40 ligand, homology modelling by ourselves and others reveals that th e said sequences are part of a loop, in similarity to all RGD sequence s found in proteins with established adhesion function and known 3-dim ensional structure. Likewise, inspection of all known protein 3-dimens ional structures containing an RGD sequence, and not having a document ed cell adhesion function (total of 65 separate entries) shows that su ch sequence is mostly (52/65 or 80% of cases) part of a loop. We there fore call attention to these surprising findings, discuss the possible cell adhesion role of these receptor proteins, and draw an analogy fr om the two well characterised examples, that of soluble IGF binding pr otein 1 and the transcriptional activator protein Tat of HIV, where th eir RGD sequences have been shown by site-directed mutagenesis to part icipate in cell-adhesion interactions, without prior knowledge of the location of the tripeptide, or the 3-dimensional structure of the resp ective protein. (C) 1998 Elsevier Science B.V.