NDLI: A unified genetic, computational and experimental framework identifies functionally relevant residues of the homing endonuclease I-BmoI

Content Provider	PubMed Central
Author	Kleinstiver, Benjamin P. Fernandes, Andrew D. Gloor, Gregory B. Edgell, David R.
Copyright Year	2010
Abstract	Insight into protein structure and function is best obtained through a synthesis of experimental, structural and bioinformatic data. Here, we outline a framework that we call MUSE ( m utual information, u nigenic evolution and s tructure-guided e lucidation), which facilitated the identification of previously unknown residues that are relevant for function of the GIY-YIG homing endonuclease I-BmoI. Our approach synthesizes three types of data: mutual information analyses that identify co-evolving residues within the GIY-YIG catalytic domain; a unigenic evolution strategy that identifies hyper- and hypo-mutable residues of I-BmoI; and interpretation of the unigenic and co-evolution data using a homology model. In particular, we identify novel positions within the GIY-YIG domain as functionally important. Proof-of-principle experiments implicate the non-conserved I71 as functionally relevant, with an I71N mutant accumulating a nicked cleavage intermediate. Moreover, many additional positions within the catalytic, linker and C-terminal domains of I-BmoI were implicated as important for function. Our results represent a platform on which to pursue future studies of I-BmoI and other GIY-YIG-containing proteins, and demonstrate that MUSE can successfully identify novel functionally critical residues that would be ignored in a traditional structure-function analysis within an extensively studied small domain of ∼90 amino acids.
Related Links	http://dx.doi.org/10.1093/nar/gkp1223
Starting Page	2411
File Format	PDF
ISSN	13624962
e-ISSN	13624962
Journal	Nucleic Acids Research
Issue Number	7
Volume Number	38
Language	English
Publisher	Oxford University Press
Publisher Date	2010-04-01
Access Restriction	Open
Rights Holder	Oxford University Press
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics

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A unified genetic, computational and experimental framework identifies functionally relevant residues of the homing endonuclease I-BmoI

Evolutionarily conserved and functionally important residues in the I-CeuI homing endonuclease.

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The monomeric GIY-YIG homing endonuclease I-BmoI uses a molecular anchor and a flexible tether to sequentially nick DNA

The monomeric GIY-YIG homing endonuclease I-BmoI uses a molecular anchor and a flexible tether to sequentially nick DNA

Divalent Metal Ion Differentially Regulates the Sequential Nicking Reactions of the GIY-YIG Homing Endonuclease I-BmoI

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A unified genetic, computational and experimental framework identifies functionally relevant residues of the homing endonuclease I-BmoI

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