Imperial College London
Alternate

DrMariaPanico

Faculty of Natural Sciences, Department of Life Sciences

Laboratory Manager
 
 
 
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+44 (0)20 7594 5204m.panico

 
 
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Location

 

102Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hunt:2019:10.3390/ijms20225734,
author = {Hunt, R and Hettiarachchi, G and Katneni, U and Hernandez, N and Holcomb, D and Kames, J and Alnifaidy, R and Lin, B and Hamasaki-Katagiri, N and Wesley, A and Kafri, T and Morris, C and Bouche, L and Panico, M and Schiller, T and Ibla, J and Bar, H and Ismail, A and Morris, H and Komar, A and Kimchi-Sarfaty, C},
doi = {10.3390/ijms20225734},
journal = {International Journal of Molecular Sciences},
pages = {1--18},
title = {A single synonymous variant (c.354G > A [p.P118P]) in ADAMTS13 confers enhanced specific activity},
url = {http://dx.doi.org/10.3390/ijms20225734},
volume = {20},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex vivo (~120% in comparison to wild-type) from a synonymous polymorphism variant, c.354G>A [p.P118P], of the ADAMTS13 gene, encoding a plasma protease responsible for von Willebrand Factor (VWF) degradation. In the current study, we investigated the potential mechanism(s) behind the increased protein expression levels from this variant and its effect on ADAMTS13 physico-chemical properties. Cell-free assays showed enhanced translation of the c.354G>A variant and the analysis of codon usage characteristics suggested that introduction of the frequently used codon/codon pair(s) may have been potentially responsible for this effect. Limited proteolysis, however, showed no substantial influence of altered translation on protein conformation. Analysis of post-translational modifications also showed no notable differences but identified three previously unreported glycosylation markers. Despite these similarities, p.P118P variant unexpectedly showed higher specific activity. Structural analysis using modeled interactions indicated that subtle conformational changes arising from altered translation kinetics could affect interactions between an exosite of ADAMTS13 and VWF resulting in altered specific activity. This report highlights how a single synonymous nucleotide variation can impact cellular expression and specific activity in the absence of measurable impact on protein structure.
AU  - Hunt,R
AU  - Hettiarachchi,G
AU  - Katneni,U
AU  - Hernandez,N
AU  - Holcomb,D
AU  - Kames,J
AU  - Alnifaidy,R
AU  - Lin,B
AU  - Hamasaki-Katagiri,N
AU  - Wesley,A
AU  - Kafri,T
AU  - Morris,C
AU  - Bouche,L
AU  - Panico,M
AU  - Schiller,T
AU  - Ibla,J
AU  - Bar,H
AU  - Ismail,A
AU  - Morris,H
AU  - Komar,A
AU  - Kimchi-Sarfaty,C
DO  - 10.3390/ijms20225734
EP  - 18
PY  - 2019///
SN  - 1422-0067
SP  - 1
TI  - A single synonymous variant (c.354G > A [p.P118P]) in ADAMTS13 confers enhanced specific activity
T2  - International Journal of Molecular Sciences
UR  - http://dx.doi.org/10.3390/ijms20225734
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000502786800216&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.mdpi.com/1422-0067/20/22/5734
UR  - http://hdl.handle.net/10044/1/75928
VL  - 20
ER  -
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