We probed collagen and elastin interactions with enzymes that digest them called MMPs (short for matrix metallproteinases; Palmier et al., 2010, JBC; Fulcher et al., 2011, Biochemistry; Zhao et al., 2015, Structure). Unexpectedly, two of three intertwined chains of the collagen triple-helix fitted into the narrow part of an MMP active site (Prior et al., 2016, JBC). (This work was supported by NIH grants GM057289, CA098799, and T32 GM008396 and American Heart Association grant 0855714G.)

We docked an inhibitory protein called TIMP-1 to an MMP (Arumugam et al., 2003, Biochemistry) and were surprised to learn that conformational entropy gain in TIMP-1 upon binding contributes to the high affinity (Arumugam et al., 2003, JMB). (This was supported by NIH grant GM057289).

We located where the chaperone from a tumor virus binds the chaperone Hsc70 factor (Garimella et al., 2006, Biochemistry), and found the “business end” of the viral chaperone to be dynamic (Berjanskii et al., 2002, JMB). (This was supported by American Cancer Society grant RSG98-253-4-MBC).

Publications cited:

Arumugam S, Van Doren SR. Global orientation of bound MMP-3 and N-TIMP-1 in solution via residual dipolar couplings. Biochemistry. 2003 Jul 8;42(26):7950-8. https://doi.org/10.1021/bi034545s

Arumugam S, Gao G, Patton BL, Semenchenko V, Brew K, Van Doren SR. Increased backbone mobility in beta-barrel enhances entropy gain driving binding of N-TIMP-1 to MMP-3. J Mol Biol. 2003 Mar 28;327(3):719-34. https://doi.org/10.1016/S0022-2836(03)00180-3

Berjanskii M, Riley M, Van Doren SR. Hsc70-interacting HPD loop of the J domain of polyomavirus T antigens fluctuates in ps to ns and micros to ms. J Mol Biol. 2002 Aug 16;321(3):503-16. https://doi.org/10.1016/S0022-2836(02)00631-9

Fulcher YG, Van Doren SR. Remote exosites of the catalytic domain of matrix metalloproteinase-12 enhance elastin degradation. Biochemistry. 2011 Nov 8;50(44):9488-99. https://doi.org/10.1021/bi2009807

Garimella R, Liu X, Qiao W, Liang X, Zuiderweg ER, Riley MI, Van Doren SR. Hsc70 contacts helix III of the J domain from polyomavirus T antigens: addressing a dilemma in the chaperone hypothesis of how they release E2F from pRb. Biochemistry. 2006 Jun 6;45(22):6917-29. https://doi.org/10.1021/bi060411d

Palmier MO, Fulcher YG, Bhaskaran R, Duong VQ, Fields GB, Van Doren SR. NMR and bioinformatics discovery of exosites that tune metalloelastase specificity for solubilized elastin and collagen triple helices. J Biol Chem. 2010 Oct 1;285(40):30918-30. https://doi.org/10.1074/jbc.M110.136903

Prior SH, Byrne TS, Tokmina-Roszyk D, Fields GB, Van Doren SR. Path to Collagenolysis: COLLAGEN V TRIPLE-HELIX MODEL BOUND PRODUCTIVELY AND IN ENCOUNTERS BY MATRIX METALLOPROTEINASE-12. J Biol Chem. 2016 Apr 8;291(15):7888-901. https://doi.org/10.1074/jbc.M115.703124

Zhao Y, Marcink TC, Sanganna Gari RR, Marsh BP, King GM, Stawikowska R, Fields GB, Van Doren SR. Transient collagen triple helix binding to a key metalloproteinase in invasion and development.Structure. 2015 Feb 3;23(2):257-69. https://doi.org/10.1016/j.str.2014.11.021