Sequence‐derived structural features driving proteolytic processing

Abstract

Proteolytic signaling, or regulated proteolysis, is an essential part of many important pathways such as Notch, Wnt, and Hedgehog. How the structure of the cleaved substrate regions influences the efficacy of proteolytic processing remains underexplored. Here, we analyzed the relative importance in proteolysis of various structural features derived from substrate sequences using a dataset of more than five thousand experimentally verified proteolytic events captured in CutDB. Accessibility to the solvent was recognized as an essential property of a proteolytically processed polypeptide chain. Proteolytic events were found nearly uniformly distributed among three types of secondary structure, although with some enrichment in loops. Cleavages in α-helices were found to be relatively abundant in regions apparently prone to unfolding, while cleavages in β-structures tended to be located at the periphery of β-sheets. Application of the same statistical procedures to proteolytic events divided into separate sets according to the catalytic classes of proteases proved consistency of the results and confirmed that the structural mechanisms of proteolysis are universal. The estimated prediction power of sequence-derived structural features, which turned out to be sufficiently high, presents a rationale for their use in bioinformatic prediction of proteolytic events.

CleavPredict: A Platform for Reasoning about Matrix Metalloproteinases Proteolytic Events

“…The cleavage site needs to be accessible at the protein surface. Recently, it has been shown that this property as measured by an absolute solvent accessibility index is essential for a proteolytic event to occur [ 2 ]. However, cleavage sites that are hidden in native proteins can become accessible as a result of unfolding, allosteric effects, and other proteolytic activity.…”

Sequence and Conformational Specificity in Substrate Recognition

“…Initially, we examined the cleavage sites in the available Kunitz domain structures for solvent accessibility and for flexibility as evidenced by B-factors, two structural descriptors that we have previously identified as being important in proteolysis (50,51). However, given the close structural similarity among Kunitz domains, we did not find correlative differences in these descriptors in our data set.…”

High-Throughput Multiplexed Peptide-Centric Profiling Illustrates Both Substrate Cleavage Redundancy and Specificity in the MMP Family

“…Because of the effect of the MMP auxiliary domains, structural constraints and special-temporal differences between the substrate and the protease, peptide cleavage in in vitro assays may not always predict that the same sequence is targeted in a natural protein. These limitations are discussed in a detail in our additional manuscripts (Belushkin, et al, 2014; Kazanov, et al, 2011; Kumar, et al, 2015). …”