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 motif in 67 integral plasma membrane proteins (in 48 extracellularly, and in the remaining 19 intracellularly), which are bona fide receptors, and none of them has thus far been considered as a cell adhesion protein. The 3-dimensional structure of one of these, the rat neonatal Fc receptor, is known and its extracellular RGD sequence is in an adhesion-like loop, a fact that went unnoticed in the original papers. In a few other cases, e.g. rat and mouse growth hormone receptor, and mouse CD40 ligand, homology modelling by ourselves and others reveals that the said sequences are part of a loop, in similarity to all RGD sequences found in proteins with established adhesion function and known 3-dimensional structure. Likewise, inspection of all known protein 3-dimensional structures containing an RGD sequence, and not having a documented cell adhesion function (total of 65 separate entries) shows that such sequence is mostly (52/65 or 80% of cases) part of a loop. We therefore call attention to these surprising findings, discuss the possible cell adhesion role of these receptor proteins, and draw an analogy from the two well characterised examples, that of soluble IGF binding protein 1 and the transcriptional activator protein Tat of HIV, where their RGD sequences have been shown by site-directed mutagenesis to participate in cell-adhesion interactions, without prior knowledge of the location of the tripeptide, or the 3-dimensional structure of the respective protein.
Papadopoulos
G K
GK
Department of Internal Medicine, University of Ioannina Medical School, Greece.
Ouzounis
C
C
Eliopoulos
E
E
D000818:Animals; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000502:physiology*; D002645:Chickens; D006224:Cricetinae; D016208:Databases, Factual; D006801:Humans; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000502:physiology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D013552:Swine
D015815:Cell Adhesion Molecules; D009842:Oligopeptides; D011956:Receptors, Cell Surface; C047981:arginyl-glycyl-aspartic acid