Who climbs the tryptophan ladder? On the structure and function of the WSXWS motif in cytokine receptors and thrombospondin repeats

For decades, a spectacular structural motif has been the focus of research in two families of animal membrane proteins: the hematopoietic cytokine type I receptors (HCR) and the thrombospondin repeat type 1 (TSR-1) domain containing proteins. Although these families include some of the best-studied and pharmaceutically most interesting human proteins, the function of the motif remains elusive. Here we show that the molecular details of the motifs are the same; that it has arisen through convergent evolution, and we argue that the same ligand binding function is maintained and suggest that the ligand can be found in the extracellular matrix (ECM). We term the motif the tryptophan ladder and suggest a function based on a comparative analysis.