Hint auto-proteolytic protein-processing domains

1. Inteins
2. Hog Hint domains
3. A-type Bacterial intein-like (BIL) domains
4. B-type BIL domains

All Hint domain types are 130 to 160 amino acid long, sharing 4-6 conserved sequence motifs. Intein and Hog Hint domain families also share the same structural fold and active site arrangement [4]. BIL domains probably have this fold as well. Hint domains have similar biochemical reactions, by which they remove themselves from their protein precursors [1].

However, Hint domains differ from each other in some sequence features, in the protein types and positions in which they are integrated, and in their known and proposed biological roles.

Inteins are selfish genetic elements, embedded in-frame within highly conserved regions of essential proteins in species from the three domains of life. The intein domain is translated with its protein host, and excises itself out by efficient protein-splicing of its two flanks with a peptide bond. Thus, the intein gene is inserted in gene regions that are unlikely to be lost or modified, but does not interfere with the function of its protein host [5,6]. Protein-splicing depends on conserved active-site residues within the intein, and on an invariable Cys, Ser or Thr nucleophilic C'-flanking residue following the intein domain [1]. Hog Hint domains are found in animal Hedgehog proteins and in a few nematode protein families. Unlike inteins, Hog domains have a role in the normal maturation process of their protein hosts. In Hedgehog proteins, the Hint domain is followed by a cholesterol-binding domain, and autocatalyses its cleavage from the N' Hedge domain by attaching a cholesterol molecule to it. The released Hedge domain is further modified and secreted from the cell as a developmental signal [3]. A-type and B-type BIL domains are integrated in non-conserved, hyper-variable proteins, some of which are extracellular. Until now, these domains were only found in bacterial species. BIL domains may contribute to their host variability by protein-splicing, cleavage and ligation [2,7]. The two BIL types are distinguished from each other, and from other Hint domains, by characteristic sequence features. A- type BIL domains are capable of protein-splicing, and of N'- or C'- cleavages, and B-type BIL domains were found to auto-cleave at either their N' or C' ends [8].

We maintain WWW sites for the intein and BIL protein domains, where more detailed information and furher links can be found.

References
[1] Paulus, H. (2000) Protein Splicing and Related Forms of Protein Autoprocessing. Annu. Rev. Biochem. 69, 447-496.
[2] Amitai, G. et al. (2003) Distribution and function of new bacterial intein-like protein domains. Molecular. Microbiology 47, 61-73
[3] Mann, R.K., Beachy, P.A. (2004) Novel lipid modifications of secreted protein signals. Annu Rev Biochem 73, 891-923
[4] Hall, T.M. et al. (1997) Crystal Structure of a Hedgehog Autoprocessing Domain: Homology between Hedgehog and Self-Splicing Proteins. Cell 91, 85-97
[5] Liu, X.Q. (2000) Protein-splicing intein: Genetic mobility, origin, and evolution. Annu Rev Genet 34, 61-76
[6] Pietrokovski, S. (2001) Intein spread and extinction in evolution. Trends Genet 17, 465-472
[7] Southworth, M.W. and Yin, J., Perler, F.B. (2004) Rescue of protein splicing activity from a Magnetospirillum magnetotacticum intein-like element. Biochem Soc Trans 32, 250-254
[8] Dassa, B., Haviv, H., Amitai, G., Pietrokovski, S. (2004) Protein splicing and auto-cleavage of bacterial intein-like domains lacking a C'-flanking nucleophilic residue. J Biol Chem published online ahead of print as doi:10.1074/jbc.M404562200