Abstract

Extracellular matrix mechanics influence diverse cellular functions, yet surprisingly little is known about the mechanical properties of their constituent collagens. While collagen type IV is an integral component of basement membranes, it has received far less attention than the more abundant fibrillar collagens. In this work, we used atomic force microscopy to image different collagen types and analyze their sequence-dependent mechanics. By analyzing their flexibility in a sequence-dependent manner, we learned that discontinuities in the triple-helix-defining sequence (Gly-X-Y) in collagen IV lead to a generally more flexible polymer with notable flexible “hinges” that correlate with non-helical regions. We contrast these findings by studying collagen III - a continuously triple-helical collagen - in which we found that it also displays variable flexibility along its contour, most notably possessing a high flexibility region near the matrix metalloprotease (MMP) binding site. This result represents the first demonstration of a unique mechanical signature of the MMP site along collagen and offers the opportunity to examine the interplay between sequence, thermal stability, and mechanical properties. Surprisingly, we found that proline content did not correlate with local flexibility in either collagen type. We also found that physiologically relevant changes in pH and chloride concentration did not alter the flexibility of collagen IV, indicating such environmental changes are not used to control its compaction during secretion. Furthermore, we found that collagen IV exhibits oscillatory local curvature, while collagen III displays no strong preferred curvature along its contour. Our sequence-dependent curvature results show that the collagenous domain of collagen IV is structurally different than collagen III, beyond just enhanced flexibility, and we discuss possibilities for this structural profile - it could be conveying information related to collagen IV's mechanism of assembly.

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