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  Changes in active site histidine hydrogen bonding trigger cryptochrome activation

Ganguly, A., Manahan, C. C., Top, D., Yee, E. F., Lin, C., Young, M. W., et al. (2016). Changes in active site histidine hydrogen bonding trigger cryptochrome activation. Proceedings of the National Academy of Sciences of the United States of America, 113(36), 10073-10078. doi:10.1073/pnas.1606610113.

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 Creators:
Ganguly, Abir1, Author              
Manahan, Craig C.2, Author
Top, Deniz3, Author
Yee, Estella F.2, Author
Lin, Changfan2, Author
Young, Michael W.3, Author
Thiel, Walter1, Author              
Crane, Brian R.2, Author
Affiliations:
1Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445590              
2Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, ou_persistent22              
3Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, ou_persistent22              

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 Abstract: Cryptochrome (CRY) is the principal light sensor of the insect circadian clock. Photoreduction of the Drosophila CRY (dCRY) flavin cofactor to the anionic semiquinone (ASQ) restructures a C-terminal tail helix (CTT) that otherwise inhibits interactions with targets that include the clock protein Timeless (TIM). All-atom molecular dynamics (MD) simulations indicate that flavin reduction destabilizes the CTT, which undergoes large-scale conformational changes (the CTT release) on short (25 ns) timescales. The CTT release correlates with the conformation and protonation state of conserved His378, which resides between the CTT and the flavin cofactor. Poisson-Boltzmann calculations indicate that flavin reduction substantially increases the His378 pKa. Consistent with coupling between ASQ formation and His378 protonation, dCRY displays reduced photoreduction rates with increasing pH; however, His378Asn/Arg variants show no such pH dependence. Replica-exchange MD simulations also support CTT release mediated by changes in His378 hydrogen bonding and verify other responsive regions of the protein previously identified by proteolytic sensitivity assays. His378 dCRY variants show varying abilities to light-activate TIM and undergo self-degradation in cellular assays. Surprisingly, His378Arg/Lys variants do not degrade in light despite maintaining reactivity toward TIM, thereby implicating different conformational responses in these two functions. Thus, the dCRY photosensory mechanism involves flavin photoreduction coupled to protonation of His378, whose perturbed hydrogen-bonding pattern alters the CTT and surrounding regions.

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Language(s): eng - English
 Dates: 2016-04-262016-08-222016-09-06
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1073/pnas.1606610113
 Degree: -

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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Acad. Sci. USA
  Other : Proc. Acad. Sci. U.S.A.
  Abbreviation : PNAS
Source Genre: Journal
 Creator(s):
Truhlar, Donald G.1, Editor
Affiliations:
1 University of Minnesota, Minneapolis, MN, ou_persistent22            
Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 113 (36) Sequence Number: - Start / End Page: 10073 - 10078 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230