Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex.
Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex.
复制标题
DOI：
10.3389/fphar.2021.602206
复制
发表时间：
2021
影响因子：
5.6
通讯作者：
Cardozo T
中科院分区：
文献类型：
--
作者：
Lavinda O;Manga P;Orlow SJ;Cardozo T
酪氨酸酶（TYR）是一种含铜的单加氧酶，对黑素细胞的功能至关重要。其表达或活性的改变导致皮肤、头发和眼睛颜色的变化，并成为多种致病性色素表型的基础，包括几种形式的眼皮肤白化病（OCA）。许多这些表型与单个错义突变有关，导致TYR中的单核苷酸变异和多态性（snv）。我们之前发现两个TYR同源物TYRP1和TYRP2调节TYR活性并稳定TYR蛋白。因此，为了研究TYR、TYRP1和TYRP2是否与各种异质配合物具有生物物理相容性，我们将TYR的高质量3D模型与TYRP1的晶体结构和TYRP2的高质量3D模型进行了计算对接。值得注意的是，得到的TYRP1- TYRP1异源二聚体与TYRP2异源二聚体在结构和能量上是互补的，TYRP1和TYRP2对接到TYR上不同的相邻表面，这是TYRP1-TYRP2之间第三个实际的蛋白质界面。因此，3D模型与异三聚体tyr1 - tyrp1 - tyrp2复合物兼容。此外，这种异三聚体tyr1 - tyrp1 - tyrp2将每个折叠酶结构域的c端定位在理想位置，使其c端跨膜螺旋形成假定的膜内三螺旋束。最后，致病的TYR突变导致OCA1A聚集在异三聚体复合物外围的一个未被占用的蛋白质界面上，这也使TYR在生物化学上不稳定，这表明这可能是OCA2（一个阴离子通道）的对接位点。致病性OCA2突变导致的表型与OCA1A TYR突变产生的表型相似。由于脊椎动物细胞膜系统的复杂环境，这种复合物可能难以在体外检测到，但我们的研究结果支持在黑色素形成中存在异三聚体复合物。
Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.
登录
查看更多内容
影响因子：
4.6
作者：
Cai X;Thinn AMM;Wang Z;Shan H;Zhu J
通讯作者：
Zhu J
DOI：
10.1111/j.1600-0749.1994.tb00054.x
发表时间：
1994-08-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
KOBAYASHI, T;URABE, K;HEARING, VJ
通讯作者：
HEARING, VJ
DOI：
10.1016/s0097-8485(99)00044-3
发表时间：
2000-01-01
期刊：
COMPUTERS & CHEMISTRY
影响因子：
--
作者：
Cardozo, T;Batalov, S;Abagyan, R
通讯作者：
Abagyan, R
DOI：
10.1056/nejmoa0908547
发表时间：
2010-05-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jin Y;Birlea SA;Fain PR;Gowan K;Riccardi SL;Holland PJ;Mailloux CM;Sufit AJ;Hutton SM;Amadi-Myers A;Bennett DC;Wallace MR;McCormack WT;Kemp EH;Gawkrodger DJ;Weetman AP;Picardo M;Leone G;Taïeb A;Jouary T;Ezzedine K;van Geel N;Lambert J;Overbeck A;Spritz RA
通讯作者：
Spritz RA
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M