Department of Chemistry, Boston University, Boston, MA 02215.
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20814.
Proc Natl Acad Sci U S A. 2022 Dec 27;119(52):e2212207119. doi: 10.1073/pnas.2212207119. Epub 2022 Dec 20.
The 99-residue C-terminal domain of amyloid precursor protein (APP-C99), precursor to amyloid beta (A), is a transmembrane (TM) protein containing intrinsically disordered N- and C-terminal extramembrane domains. Using molecular dynamics (MD) simulations, we show that the structural ensemble of the C99 monomer is best described in terms of thousands of states. The C99 monomer has a propensity to form -strand in the C-terminal extramembrane domain, which explains the slow spin relaxation times observed in paramagnetic probe NMR experiments. Surprisingly, homodimerization of C99 not only narrows the conformational ensemble from thousands to a few states through the formation of metastable -strands in extramembrane domains but also stabilizes extramembrane -helices. The extramembrane domain structure is observed to dramatically impact the homodimerization motif, resulting in the modification of TM domain conformations. Our study provides an atomic-level structural basis for communication between the extramembrane domains of the C99 protein and TM homodimer formation. This finding could serve as a general model for understanding the influence of disordered extramembrane domains on TM protein structure.
淀粉样前体蛋白（APP-C99）的 99 个残基 C 端结构域是淀粉样β（A）的前体，是一种跨膜（TM）蛋白，含有固有无序的 N 端和 C 端胞外结构域。通过分子动力学（MD）模拟，我们表明 C99 单体的结构集合最好用数千种状态来描述。C99 单体在 C 端胞外结构域中具有形成β-折叠的倾向，这解释了顺磁探针 NMR 实验中观察到的较慢的自旋弛豫时间。令人惊讶的是，C99 同源二聚体不仅通过形成在胞外结构域中的亚稳态β-折叠将构象集合从数千种缩小到几种状态，而且还稳定了胞外α-螺旋。观察到胞外结构域结构对同源二聚体基序有显著影响，导致 TM 结构域构象的改变。我们的研究为 C99 蛋白的胞外结构域之间的通讯和 TM 同源二聚体形成提供了原子水平的结构基础。这一发现可以作为理解无序胞外结构域对 TM 蛋白结构影响的一般模型。
