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Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences

Cysteine oxidation states of extracellular proteins participate in functional regulation and in disease pathophysiology. In the most common inherited dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mutations in NOTCH3 that alter extrace...

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Detalles Bibliográficos
Autores principales: Cartee, Naw May Pearl, Lee, Soo Jung, Young, Kelly Z., Zhang, Xiaojie, Wang, Michael M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115637/
https://www.ncbi.nlm.nih.gov/pubmed/35409031
http://dx.doi.org/10.3390/ijms23073671
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author Cartee, Naw May Pearl
Lee, Soo Jung
Young, Kelly Z.
Zhang, Xiaojie
Wang, Michael M.
author_facet Cartee, Naw May Pearl
Lee, Soo Jung
Young, Kelly Z.
Zhang, Xiaojie
Wang, Michael M.
author_sort Cartee, Naw May Pearl
collection PubMed
description Cysteine oxidation states of extracellular proteins participate in functional regulation and in disease pathophysiology. In the most common inherited dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mutations in NOTCH3 that alter extracellular cysteine number have implicated NOTCH3 cysteine states as potential triggers of cerebral vascular smooth muscle cytopathology. In this report, we describe a novel property of the second EGF-like domain of NOTCH3: its capacity to alter the cysteine redox state of the NOTCH3 ectodomain. Synthetic peptides corresponding to this sequence (NOTCH3 N-terminal fragment 2, NTF2) readily reduce NOTCH3 N-terminal ectodomain polypeptides in a dose- and time-dependent fashion. Furthermore, NTF2 preferentially reduces regional domains of NOTCH3 with the highest intensity against EGF-like domains 12–15. This process requires cysteine residues of NTF2 and is also capable of targeting selected extracellular proteins that include TSP2 and CTSH. CADASIL mutations in NOTCH3 increase susceptibility to NTF2-facilitated reduction and to trans-reduction by NOTCH3 produced in cells. Moreover, NTF2 forms complexes with the NOTCH3 ectodomain, and cleaved NOTCH3 co-localizes with the NOTCH3 ectodomain in cerebral arteries of CADASIL patients. The potential for NTF2 to reduce vascular proteins and the enhanced preference for it to trans-reduce mutant NOTCH3 implicate a role for protein trans-reduction in cerebrovascular pathological states such as CADASIL.
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spelling pubmed-91156372022-05-19 Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences Cartee, Naw May Pearl Lee, Soo Jung Young, Kelly Z. Zhang, Xiaojie Wang, Michael M. Int J Mol Sci Article Cysteine oxidation states of extracellular proteins participate in functional regulation and in disease pathophysiology. In the most common inherited dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mutations in NOTCH3 that alter extracellular cysteine number have implicated NOTCH3 cysteine states as potential triggers of cerebral vascular smooth muscle cytopathology. In this report, we describe a novel property of the second EGF-like domain of NOTCH3: its capacity to alter the cysteine redox state of the NOTCH3 ectodomain. Synthetic peptides corresponding to this sequence (NOTCH3 N-terminal fragment 2, NTF2) readily reduce NOTCH3 N-terminal ectodomain polypeptides in a dose- and time-dependent fashion. Furthermore, NTF2 preferentially reduces regional domains of NOTCH3 with the highest intensity against EGF-like domains 12–15. This process requires cysteine residues of NTF2 and is also capable of targeting selected extracellular proteins that include TSP2 and CTSH. CADASIL mutations in NOTCH3 increase susceptibility to NTF2-facilitated reduction and to trans-reduction by NOTCH3 produced in cells. Moreover, NTF2 forms complexes with the NOTCH3 ectodomain, and cleaved NOTCH3 co-localizes with the NOTCH3 ectodomain in cerebral arteries of CADASIL patients. The potential for NTF2 to reduce vascular proteins and the enhanced preference for it to trans-reduce mutant NOTCH3 implicate a role for protein trans-reduction in cerebrovascular pathological states such as CADASIL. MDPI 2022-03-27 /pmc/articles/PMC9115637/ /pubmed/35409031 http://dx.doi.org/10.3390/ijms23073671 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cartee, Naw May Pearl
Lee, Soo Jung
Young, Kelly Z.
Zhang, Xiaojie
Wang, Michael M.
Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
title Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
title_full Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
title_fullStr Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
title_full_unstemmed Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
title_short Trans-Reduction of Cerebral Small Vessel Disease Proteins by Notch-Derived EGF-like Sequences
title_sort trans-reduction of cerebral small vessel disease proteins by notch-derived egf-like sequences
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115637/
https://www.ncbi.nlm.nih.gov/pubmed/35409031
http://dx.doi.org/10.3390/ijms23073671
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