The Convergence of the Hedgehog/Intein Fold in Different Protein Splicing Mechanisms

Author:

Beyer, Hannes M [ORCID]

Virtanen, Salla I

Aranko, A Sesilja

Mikula, Kornelia M

Lountos,George [ORCID]

Wlodawer,Alexander

Ollila, O H Samuli [ORCID]

Iwaï, Hideo [ORCID]
Author Address

Institute of Biotechnology, University of Helsinki, P.O. Box 65, FIN-00014 Helsinki, Finland., Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Macromolecular Crystallography Laboratory, National Cancer Institute, Frederick, MD 21702, USA.,

Abstract:

Protein splicing catalyzed by inteins utilizes many different combinations of amino-acid types at active sites. Inteins have been classified into three classes based on their characteristic sequences. We investigated the structural basis of the protein splicing mechanism of class 3 inteins by determining crystal structures of variants of a class 3 intein from Mycobacterium chimaera and molecular dynamics simulations, which suggested that the class 3 intein utilizes a different splicing mechanism from that of class 1 and 2 inteins. The class 3 intein uses a bond cleavage strategy reminiscent of proteases but share the same Hedgehog/INTein (HINT) fold of other intein classes. Engineering of class 3 inteins from a class 1 intein indicated that a class 3 intein would unlikely evolve directly from a class 1 or 2 intein. The HINT fold appears as structural and functional solution for trans-peptidyl and trans-esterification reactions commonly exploited by diverse mechanisms using different combinations of amino-acid types for the active-site residues.

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