20 PROTEINS CONTAINING A C-TERMINAL SOCS BOX FORM-5 STRUCTURAL CLASSES

The four members of the recently identified suppressor of cytokines si gnaling family (SOCS-1, SOCS-2, SOCS-3, and CIS, where CIS is cytokine -inducible SH2-containing protein) appear, by various means, to negati vely regulate cytokine signal transduction. Structurally, the SOCS pro teins are composed of an N-terminal region of variable length and amin o acid composition, a central SH2 domain, and a previously unrecognize d C-terminal motif that we have called the SOCS box. By using the SOCS box amino acid sequence consensus, we have searched DNA databases and have identified a further 16 proteins that contain this motif. These proteins fall into five classes based on the protein motifs found N-te rminal of the SOCS box. In addition to four new SOCS proteins (SOCS-4 to SOCS-7) containing an SH2 domain and a SOCS box, we describe three new families of proteins that contain either WD-4O repeats (WSB-1 and -2), SPRY domains (SSB-1 to -3) or ankyrin repeats (ASB-1 to -3) N-ter minal of the SOCS box. In addition, we show that a class of small GTPa ses also contains a SOCS box. The expression of representative members of each class of proteins differs markedly, as does the regulation of expression by cytokines. The function of the WSB, SSB, and ASB protei n families remains to be determined.