The residues 4 to 6 at the N-terminus in particular modulate fibril propagation of β_(2)-microglobulin  

作　　者：Haibin Dang Zhixian Chen Wang Chen Xudong Luo Pan Liu Liqiang Wang Jie Chen Xuhai Tang Zhengzhi Wang Yi Liang 

机构地区：[1]Hubei Key Laboratory of Cell Homeostasis,College of Life Sciences,Wuhan University,Wuhan 430072,China [2]Wuhan University Shenzhen Research Institute,Shenzhen 518057,China [3]School of Civil Engineering,Wuhan University,Wuhan 430072,China

出　　处：《Acta Biochimica et Biophysica Sinica》2022年第2期187-198,共12页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the National Natural Science Foundation of China(Nos.32071212,31770833,and 31570779)to Y.L.;Key Project of Basic Research,Science and Technology R&D Fund of Shenzhen(No.JCYJ20200109144418639)to Y.L.;the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(No.ZNJC201934)to Y.L.

摘　　要：The ΔN6 truncation is the main posttranslational modification of β_(2)-microglobulin( β_(2)M)found in dialysis-related amyloid.Investigation of the interaction of wild-type(WT) β_(2)M with N-terminally truncated variants is therefore of medical relevance.However,it is unclear which residues among the six residues at the N-terminus are crucial to the interactions and the modulation of amyloid fibril propagation of β_(2)M.We herein analyzed homo-and heterotypic seeding of amyloid fibrils of WT human β_(2)M and its N-terminally-truncated variantsΔN1 toΔN6,lacking up to six residues at the N-terminus.At acidic pH 2.5,we produced amyloid fibrils in vitro from recombinant,WT β_(2)M and its six truncated variants,and found thatΔN6 β_(2)M fibrils exhibit a significantly lower conformational stability than WT β_(2)M fibrils.Importantly,under more physiological conditions(pH 6.2),we assembled amyloid fibrils in vitro only from recombinant,ΔN4,ΔN5,andΔN6 β_(2)M but not from WT β_(2)M and its three truncated variantsΔN1 toΔN3.Notably,the removal of the six,five or four residues at the N-terminus leads to enhanced fibril formation,and homoand heterotypic seeding ofΔN6 fibrils strongly promotes amyloid fibril formation of WT β_(2)M and its six truncated variants,including at more physiological pH 6.2.Collectively,these results demonstrated that the residues 4 to 6 at the N-terminus particularly modulate amyloid fibril propagation of β_(2)M and the interactions of WT β_(2)M with Nterminally truncated variants,potentially indicating the direct relevance to the involvement of the protein’s aggregation in dialysis-related amyloidosis.

关 键 词：humanβ_(2)-microglobulin amyloid fibril conformational stability truncated variant fibril propagation atomic force microscopy 

分 类 号：Q51[生物学—生物化学]