scholarly journals Twenty years of bioinformatics research for protease-specific substrate and cleavage site prediction: a comprehensive revisit and benchmarking of existing methods

2018 ◽  
Vol 20 (6) ◽  
pp. 2150-2166 ◽  
Author(s):  
Fuyi Li ◽  
Yanan Wang ◽  
Chen Li ◽  
Tatiana T Marquez-Lago ◽  
André Leier ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Scoring Function ◽  
Proteolytic Cleavage ◽  
Prediction Performance ◽  
Specific Substrate ◽  
Cleavage Sites ◽  
Cell Cycle Protein ◽  
Computational Approaches ◽  
Site Prediction ◽  
Cleavage Site Prediction

Abstract The roles of proteolytic cleavage have been intensively investigated and discussed during the past two decades. This irreversible chemical process has been frequently reported to influence a number of crucial biological processes (BPs), such as cell cycle, protein regulation and inflammation. A number of advanced studies have been published aiming at deciphering the mechanisms of proteolytic cleavage. Given its significance and the large number of functionally enriched substrates targeted by specific proteases, many computational approaches have been established for accurate prediction of protease-specific substrates and their cleavage sites. Consequently, there is an urgent need to systematically assess the state-of-the-art computational approaches for protease-specific cleavage site prediction to further advance the existing methodologies and to improve the prediction performance. With this goal in mind, in this article, we carefully evaluated a total of 19 computational methods (including 8 scoring function-based methods and 11 machine learning-based methods) in terms of their underlying algorithm, calculated features, performance evaluation and software usability. Then, extensive independent tests were performed to assess the robustness and scalability of the reviewed methods using our carefully prepared independent test data sets with 3641 cleavage sites (specific to 10 proteases). The comparative experimental results demonstrate that PROSPERous is the most accurate generic method for predicting eight protease-specific cleavage sites, while GPS-CCD and LabCaS outperformed other predictors for calpain-specific cleavage sites. Based on our review, we then outlined some potential ways to improve the prediction performance and ease the computational burden by applying ensemble learning, deep learning, positive unlabeled learning and parallel and distributed computing techniques. We anticipate that our study will serve as a practical and useful guide for interested readers to further advance next-generation bioinformatics tools for protease-specific cleavage site prediction.

scholarly journals Proteolytic Cleavage of Bovine Adenovirus 3-Encoded pVIII

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Amit Gaba ◽  
Lisanework Ayalew ◽  
Niraj Makadiya ◽  
Suresh Tikoo
Keyword(s):  
Cleavage Site ◽  
Virus Assembly ◽  
Proteolytic Cleavage ◽  
Efficient Production ◽  
Cleavage Sites ◽  
Bovine Adenovirus ◽  
Protease Cleavage Site ◽  
Protease Cleavage ◽  
Protease Cleavage Sites ◽  
Single Protease

ABSTRACT Proteolytic maturation involving cleavage of one nonstructural and six structural precursor proteins including pVIII by adenovirus protease is an important aspect of the adenovirus life cycle. The pVIII encoded by bovine adenovirus 3 (BAdV-3) is a protein of 216 amino acids and contains two potential protease cleavage sites. Here, we report that BAdV-3 pVIII is cleaved by adenovirus protease at both potential consensus protease cleavage sites. Usage of at least one cleavage site appears essential for the production of progeny BAdV-3 virions as glycine-to-alanine mutation of both protease cleavage sites appears lethal for the production of progeny virions. However, mutation of a single protease cleavage site of BAdV-3 pVIII significantly affects the efficient production of infectious progeny virions. Further analysis revealed no significant defect in endosome escape, genome replication, capsid formation, and virus assembly. Interestingly, cleavage of pVIII at both potential cleavage sites appears essential for the production of stable BAdV-3 virions as BAdV-3 expressing pVIII containing a glycine-to-alanine mutation of either of the potential cleavage sites is thermolabile, and this mutation leads to the production of noninfectious virions. IMPORTANCE Here, we demonstrated that the BAdV-3 adenovirus protease cleaves BAdV-3 pVIII at both potential protease cleavage sites. Although cleavage of pVIII at one of the two adenoviral protease cleavage sites is required for the production of progeny virions, the mutation of a single cleavage site of pVIII affects the efficient production of infectious progeny virions. Further analysis indicated that the mutation of a single protease cleavage site (glycine to alanine) of pVIII produces thermolabile virions, which leads to the production of noninfectious virions with disrupted capsids. We thus provide evidence about the requirement of proteolytic cleavage of pVIII for production of infectious progeny virions. We feel that our study has significantly advanced the understanding of the requirement of adenovirus protease cleavage of pVIII.

scholarly journals Identification of the cleavage sites in the α6A integrin subunit: structural requirements for cleavage and functional analysis of the uncleaved α6Aβ1 integrin

1997 ◽  
Vol 324 (1) ◽  
pp. 263-272 ◽  
Author(s):  
Gepke O. DELWEL ◽  
Ingrid KUIKMAN ◽  
Roel C. van der SCHORS ◽  
Annemieke A. de MELKER ◽  
Arnoud SONNENBERG
Keyword(s):  
Cleavage Site ◽  
K562 Cells ◽  
Proteolytic Cleavage ◽  
Human Platelets ◽  
Light Chains ◽  
Integrin Subunit ◽  
Cleavage Sites ◽  
Wild Type ◽  
Proper Position ◽  
Arginine Residues

The α6A and α6B integrin subunits are proteolytically cleaved during biosynthesis into a heavy chain (120 kDa) that is disulphide-linked to one of two light chains (31 or 30 kDa). Analysis of the structure of the α6A subunit on the carcinoma cell line T24 and human platelets demonstrated that the two light chains of α6 are not differentially glycosylated products of one polypeptide. Rather they possess different polypeptide backbones, which presumably result from proteolytic cleavage at distinct sites in the α6 precursor. Mutations were introduced in the codons for the R876KKR879, E883K884, R890K891 and R898K899 sequences, the potential proteolytic cleavage sites, and wild-type and mutant α6A cDNAs were transfected into K562 cells. The mutant α6A integrin subunits were expressed in association with endogenous β1 at levels comparable to that of wild-type α6Aβ1. A single α6 polypeptide chain (150 kDa) was precipitated from transfectants expressing α6A with mutations or deletions in the RKKR sequence. Mutations in the EK sequence yielded α6A subunits that were cleaved once into a heavy and a light chain, whereas α6A subunits with mutations in one of the two RK sequences were, like wild-type α6A, cleaved into one heavy and two light chains. Thus a change in the RKKR sequence prevents the cleavage of α6. The EK site is the secondary cleavage site, which is used only when the primary site (RKKR) is intact. Microsequencing of the N-termini of the two α6A light chains from platelets demonstrated that cleavage occurs after Arg879 and Lys884. Because α6RKKG, α6GKKR and α6RGGR subunits were not cleaved it seems that both the arginine residues and the lysine residues are essential for cleavage of RKKR. α6A mutants with the RKKR sequence shifted to the EK site, in such a way that the position of the arginine residue after which cleavage occurs corresponds exactly to Lys884, were partly cleaved, whereas α6A mutants with the RKKR sequence shifted to other positions in the α6A subunit, including one in which it was shifted two residues farther than the EK cleavage site, were not cleaved. In addition, α6A mutants with an α5-like cleavage site, i.e. arginine, lysine and histidine residues at positions -1, -2 and -6, were not cleaved. Thus both an intact RKKR sequence and its proper position are essential. After activation by the anti-β1 stimulatory monoclonal antibody TS2/16, both cleaved and uncleaved α6Aβ1 integrins bound to laminin-1. The phorbol ester PMA, which activates cleaved wild-type and mutant α6Aβ1, did not activate uncleaved α6Aβ1. Thus uncleaved α6Aβ1 is capable of ligand binding, but not of inside-out signalling. Our results suggest that cleavage of α6 is required to generate a proper conformation that enables the affinity modulation of the α6Aβ1 receptor by PMA.

Toward Computer-Based Cleavage Site Prediction of Cysteine Endopeptidases

2003 ◽  
Vol 384 (6) ◽  
Author(s):  
T. Lohmüller ◽  
D. Wenzler ◽  
S. Hagemann ◽  
W. Kieß ◽  
C. Peters ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Site Prediction ◽  
Computer Based ◽  
Cysteine Endopeptidases ◽  
Cleavage Site Prediction

HIV-1 protease cleavage site prediction based on amino acid property

2009 ◽  
Vol 30 (1) ◽  
pp. 33-39 ◽  
Author(s):  
Bing Niu ◽  
Lin Lu ◽  
Liang Liu ◽  
Tian Hong Gu ◽  
Kai-Yan Feng ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cleavage Site ◽  
Amino Acid Property ◽  
Acid Property ◽  
Site Prediction ◽  
Protease Cleavage Site ◽  
Protease Cleavage ◽  
Cleavage Site Prediction ◽  
Hiv 1
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