Peripheral Associations with Lipid Bilayers

We discovered dual modes of bilayer binding by proteolytic enzymes MMP-12 (Koppisetti et al., 2014, Nat. Comms.), proMMP-7 (Prior et al., 2015, Structure), and MT1-MMP (Marcink et al., 2019, Structure). The movie shows an example of the MT1-MMP bound to a nanodisc. Anionic lipids trigger membrane insertion and reorientation of proMMP-7. Bilayered micelles could trigger allosteric maturation of proMMP-7 to MMP-7. (This was supported by NIH grant GM057289, plus CA098799).

Binding and Activation by Carbohydrates from Cell Surfaces

We captured the dynamic associations of polyanionic carbohydrates known as glycosaminoglycans (GAGs) with two basic regions of proMMP-7 (Fulcher et al., 2017, Structure). GAG chain lengths of 16+ sugar units make GAG-triggered maturation of proMMP-7 efficient, conditions which create elongated, heterogeneous assemblies (Fulcher et al., 2014, ACS Chem. Biol.). GAGs enhance the proteolytic velocity of MMP-7 and link it to growth factors and receptors that it releases from cell surfaces. (This was supported by NIH  GM057289).

Publications cited:

Fulcher YG, Prior SH, Masuko S, Li L, Pu D, Zhang F, Linhardt RJ, Van Doren SR. Glycan Activation of a Sheddase: Electrostatic Recognition between Heparin and proMMP-7. Structure. 2017 Jul 5;25(7):1100-1110.e5. https://doi.org/10.1016/j.str.2017.05.019

Fulcher YG, Sanganna Gari RR, Frey NC, Zhang F, Linhardt RJ, King GM, Van Doren SR. Heparinoids activate a protease, secreted by mucosa and tumors, via tethering supplemented by allostery. ACS Chem Biol. 2014 Apr 18;9(4):957-66. https://doi.org/10.1021/cb400898t

Koppisetti RK, Fulcher YG, Jurkevich A, Prior SH, Xu J, Lenoir M, Overduin M, Van Doren SR. Ambidextrous binding of cell and membrane bilayers by soluble matrix metalloproteinase-12. Nat Commun. 2014 Nov 21;5:5552. https://doi.org/10.1038/ncomms6552

Marcink TC, Simoncic JA, An B, Knapinska AM, Fulcher YG, Akkaladevi N, Fields GB, Van Doren SR. MT1-MMP Binds Membranes by Opposite Tips of Its β Propeller to Position It for Pericellular Proteolysis. Structure. 2019 Feb 5;27(2):281-292.e6. https://doi.org/10.1016/j.str.2018.10.008

Prior SH, Fulcher YG, Koppisetti RK, Jurkevich A, Van Doren SR. Charge-Triggered Membrane Insertion of Matrix Metalloproteinase-7, Supporter of Innate Immunity and Tumors. Structure. 2015 Nov 3;23(11):2099-110. https://doi.org/10.1016/j.str.2015.08.013