THREADING ANALYSIS SUGGESTS THAT THE OBESE GENE-PRODUCT MAY BE A HELICAL CYTOKINE

The ob gene encodes a protein that, in mutant form, is associated with obesity and type II diabetes in mice, Sequence analysis has revealed no similarities to other proteins, however, and no clues as to possibl e functions, The possibility nonetheless remains that ob is functional ly or ancestrally related to other proteins, whose sequences are diver gent to the point that only a comparison of three-dimensional structur es might detect relationship, To explore this possibility, we conduct a 'threading' search of a 3-dimensional structure database, to determi ne whether the ob protein might adopt a fold similar to any known stru cture, This search reveals that the ob sequence is compatible, at a si gnificance level of P < 0.05, with structures from the family of helic al cytokines that includes interleukin-2 and growth hormone, A structu ral model of ob based upon these results is physically and biologicall y plausible and leads to testable predictions, including the predictio n that ob may activate the JAK-STAT pathway, via binding to a receptor resembling those of the cytokine family.