Molecular dynamics investigation of a redox switch in the anti-HIV protein SAMHD1.

Authors:
Kajwal Kumar Patra
Kajwal Kumar Patra
Indian Institute of Technology Bombay
Mumbai | India
Akash Bhattacharya
Akash Bhattacharya
University of Texas Health Science Center at San Antonio
San Antonio | United States
Swati Bhattacharya
Swati Bhattacharya
University of Illinois at Urbana-Champaign
United States

Proteins 2019 Apr 24. Epub 2019 Apr 24.

Department of Chemical Engineering, Indian Institute of Technology Bombay, Mumbai, India.

HIV-1 is restricted in macrophages and certain quiescent myeloid cells due to a "Scorched Earth" dNTP starvation strategy attributed to the sterile alpha motif and HD domain protein-SAMHD1. Active SAMHD1 tetramers are assembled by GTP-Mg+2-dNTP cross bridges and cleave the triphosphate groups of dNTPs at a K of ~10 μM, which is consistent with dNTP concentrations in cycling cells, but far higher than the equivalent concentration in quiescent cells. Given the substantial disparity between the dNTP concentrations required to activate SAMHD1 tetramers (~10 μM) and the dNTP concentrations in noncycling cells (~10 nM), the possibility of alternate enzymatically active forms of SAMHD1, including monomers remains open. In particular, the possibility of redox regulation of such monomers is also an open question. There have been experimental studies on the regulation of SAMHD1 by Glutathione driven redox reactions recently. Therefore, in this work, we have performed all-atom molecular dynamics simulations to study the dynamics of monomeric SAMHD1 constructs in the context of the three redox-susceptible Cysteine residues and compared them to monomers assembled within a tetramer. Our results indicate that assembly into a tetramer causes ordering of the catalytic core and increased solvent accessibility of the Catalytic Site. We have also found that glutathionylation of surface exposed C522 causes long range allosteric disruptions extending into the protein core. Finally, we see evidence suggesting a transient interaction between C522 and C341. Such a disulfide linkage has been hypothesized by experimental models, but has never been observed in crystal structures before.

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http://dx.doi.org/10.1002/prot.25701DOI Listing
April 2019

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References

(Supplied by CrossRef)
The vpx gene of simian immunodeficiency virus facilitates efficient viral replication in fresh lymphocytes and macrophage
Yu XF et al.
J Virol 1991

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