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人整合素β亚基胞质结构域中钙蛋白酶裂解相关错义突变对钙蛋白酶-整合素信号轴的影响

Repercussions of the Calpain Cleavage-Related Missense Mutations in the Cytosolic Domains of Human Integrin-β Subunits on the Calpain-Integrin Signaling Axis.

作者信息

Kizhakethil Reshma V, Varma Ashok K, Barage Sagar H, Ramesh Kumar Neelmegam, Nagarajan Kayalvizhi, Santhosh Kumar Aruni Wilson, Kamble Shashank S

机构信息

Amity Institute of Biotechnology, Amity University, Mumbai 410206, Maharashtra, India.

Advanced Centre for Treatment, Research and Education in Cancer, Kharghar, Navi Mumbai 410210, Maharashtra, India.

出版信息

Int J Mol Sci. 2025 Apr 29;26(9):4246. doi: 10.3390/ijms26094246.

DOI:10.3390/ijms26094246
PMID:40362482
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12071666/
Abstract

Calpains, calcium-dependent cytosolic cysteine proteases, perform controlled proteolysis of their substrates for various cellular and physiological activities. In different cancers, missense mutations accumulate in the genes coding for the calpain cleavage sites in various calpain substrates termed as the calpain cleavage-related mutations (CCRMs). However, the impact of such CCRMs on the calpain-substrate interaction is yet to be explored. This study focuses on the interaction of wild-type and mutant β-integrins with calpain-1 and 2 in uterine corpus endometrial carcinoma (UCEC). A total of 48 calpain substrates with 176 CCRMs were retrieved from different datasets and shortlisted on the basis of their involvement in cancer pathways. Finally, three calpain substrates, ITGB1, ITGB3, and ITGB7, were selected to assess the structural changes due to CCRMs. These CCRMs were observed towards the C-terminal of the cytoplasmic domain within the calpain cleavage site. The wild-type and mutant proteins were docked with calpain-1 and 2, followed by molecular simulation. The interaction between mutant substrates and calpains showcased variations compared to their respective wild-type counterparts. This may be attributed to mutations in the calpain cleavage sites, highlighting the importance of the cytoplasmic domain of β-integrins in the interactions with calpains and subsequent cellular signaling. Highlights: 1. Calpain cleavage-related mutations (CCRMs) can alter cellular signaling. 2. CCRMs impact the structure of C-domains of human integrin-β subunits. 3. Altered structure influences the cleavability of human integrin-β subunits by human calpains. 4. Altered cleavability impacts the cell signaling mediated through calpain-integrin-β axis. 5. Presence of CCRMS may influence the progression of uterine corpus endometrial carcinoma (UCEC).

摘要

钙蛋白酶是一种依赖钙的胞质半胱氨酸蛋白酶，可对其底物进行可控的蛋白水解，以参与各种细胞和生理活动。在不同的癌症中，编码各种钙蛋白酶底物中钙蛋白酶切割位点的基因会积累错义突变，这些突变被称为钙蛋白酶切割相关突变（CCRMs）。然而，此类CCRMs对钙蛋白酶-底物相互作用的影响尚待探索。本研究聚焦于子宫体子宫内膜癌（UCEC）中野生型和突变型β-整合素与钙蛋白酶-1和2的相互作用。从不同数据集中检索出总共48个含有176个CCRMs的钙蛋白酶底物，并根据它们在癌症通路中的参与情况进行筛选。最后，选择了三种钙蛋白酶底物ITGB1、ITGB3和ITGB7来评估CCRMs导致的结构变化。这些CCRMs出现在钙蛋白酶切割位点内细胞质结构域的C末端。将野生型和突变型蛋白与钙蛋白酶-1和2进行对接，随后进行分子模拟。与各自的野生型对应物相比，突变底物与钙蛋白酶之间的相互作用表现出差异。这可能归因于钙蛋白酶切割位点的突变，突出了β-整合素细胞质结构域在与钙蛋白酶相互作用及后续细胞信号传导中的重要性。要点：1. 钙蛋白酶切割相关突变（CCRMs）可改变细胞信号传导。2. CCRMs影响人整合素-β亚基C结构域的结构。3. 结构改变影响人钙蛋白酶对人整合素-β亚基的切割能力。4. 切割能力改变影响通过钙蛋白酶-整合素-β轴介导的细胞信号传导。5. CCRMs的存在可能影响子宫体子宫内膜癌（UCEC）的进展。

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