STATISTICAL MODELING, PHYLOGENETIC ANALYSIS AND STRUCTURE PREDICTION OF A PROTEIN SPLICING DOMAIN COMMON TO INTEINS AND HEDGEHOG PROTEINS

Inteins, introns spliced at the protein level, and the hedgehog family of proteins involved in eucaryotic development both undergo autocatal ytic proteolysis. Here, a specific and sensitive hidden Markov model ( HMM) of a protein splicing domain shared by inteins and the hedgehog p roteins has been trained and employed for further analysis. The HMM ch aracterizes the common features of this domain including the position where a site-specific DNA endonuclease domain is inserted in the major ity of the inteins, The HMM was used to identify several new putative inteins, such as that in the Methanococcus jannaschii klbA protein, an d to generate a multiple sequence alignment of sequences possessing th is domain, Phylogenetic analysis suggests that hedgehog proteins evolv ed from inteins, Secondary and tertiary structure predictions suggest that the domain has a structure similar to a beta-sandwich, Similariti es between the serine protease cleavage mechanism and the protein spli cing reaction mechanism are discussed, Examination of the locations of inteins indicates that they are not inserted randomly in an extein, b ut are often inserted at functionally important positions in the host proteins, A specific and sensitive HMM for a domain present in klbA pr oteins identified several additional bacterial and archaeal family mem bers, and analysis of the site of insertion of the intein suggests res idues that may be functionally important, This domain may play a role in formation of surface-associated protein complexes.