Cấu trúc và kích hoạt miền xuyên màng của thụ thể TSH

Springer Science and Business Media LLC - Tập 8 - Trang 1-18 - 2016
Ricardo Núñez Miguel1, Jane Sanders1, Jadwiga Furmaniak1, Bernard Rees Smith1
1FIRS Laboratories, RSR Ltd, Cardiff, UK

Tóm tắt

Thụ thể hormone kích thích tuyến giáp (TSHR) là autoantigen mục tiêu cho các autoantibody kích thích TSHR trong bệnh Graves. TSHR bao gồm: miền lặp lại giàu leucine (LRD), vùng bản lề hoặc miền cắt (CD) và miền xuyên màng (TMD). Các sắp xếp liên kết giữa LRD TSHR và autoantibody kích thích tuyến giáp M22 hoặc TSH đã được cung cấp từ cấu trúc tinh thể của phức hợp TSHR LRD–M22 và một mô hình so sánh của TSHR LRD trong phức hợp với TSH, tương ứng. Tuy nhiên, cơ chế kích hoạt của TMD TSHR và các thụ thể hormone glycoprotein khác (GPHRs) vẫn chưa được biết đến. Chúng tôi đã tạo ra các mô hình so sánh về cấu trúc của các cấu hình không hoạt động (TMD_In) và hoạt động (TMD_Ac) của TSHR, thụ thể hormone kích thích nang (FSHR) và thụ thể hormone luteinizing (LHR) TMD. Các cấu trúc của TMD_Ac và TMD_In được lấy từ các cấu trúc tinh thể GPCR lớp A mà ở đó có các cấu hình hoàn toàn hoạt động và không hoạt động. Hầu hết các mô típ bảo tồn được quan sát trong TMD GPCR cũng được thấy trong các chuỗi axit amin của TMD GPHR. Hơn nữa, hầu hết các biến dạng xoắn ốc bảo tồn trong TMD GPCR cũng được nhận thấy trong các mô hình cấu trúc TMD GPHR của chúng tôi. Phân tích các cấu trúc này đã cho phép chúng tôi đề xuất một cơ chế cho việc kích hoạt TMD của GPHR. Sự hiểu biết về cơ chế kích hoạt của TSHR bởi cả TSH và autoantibodies TSHR có khả năng hữu ích trong việc phát triển các phương pháp điều trị mới cho bệnh Graves.

Từ khóa

#TSHR #hormone kích thích tuyến giáp #bệnh Graves #thụ thể hormone glycoprotein #miền xuyên màng

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