CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module.
CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module.
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DOI：
10.1038/s41467-020-19113-0
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发表时间：
2020-11-02
影响因子：
16.6
通讯作者：
Omran H
中科院分区：
文献类型：
--
作者：
Dougherty GW;Mizuno K;Nöthe-Menchen T;Ikawa Y;Boldt K;Ta-Shma A;Aprea I;Minegishi K;Pang YP;Pennekamp P;Loges NT;Raidt J;Hjeij R;Wallmeier J;Mussaffi H;Perles Z;Elpeleg O;Rabert F;Shiratori H;Letteboer SJ;Horn N;Young S;Strünker T;Stumme F;Werner C;Olbrich H;Takaoka K;Ide T;Twan WK;Biebach L;Große-Onnebrink J;Klinkenbusch JA;Praveen K;Bracht DC;Höben IM;Junger K;Gützlaff J;Cindrić S;Aviram M;Kaiser T;Memari Y;Dzeja PP;Dworniczak B;Ueffing M;Roepman R;Bartscherer K;Katsanis N;Davis EE;Amirav I;Hamada H;Omran H
轴突动力蛋白ATP酶通过三磷酸腺苷（ATP）水解直接纤毛和鞭毛跳动。单磷酸腺苷（AMP）和二磷酸腺苷（ADP）对鞭毛跳动的调节作用尚不完全清楚。在这里，我们描述了人类和小鼠中纤毛和鞭毛相关蛋白45 （CFAP45）的缺乏，表现为运动性纤毛病，表现为完全性反位和弱精子症。cfap45缺失的纤毛和鞭毛形态和轴突超微结构正常。蛋白质组学分析将CFAP45与轴突模块联系起来，包括动力蛋白atp酶和腺苷酸激酶，以及CFAP52，其突变导致类似的纤毛病。CFAP45在体外结合AMP，与结构模型一致，确定了CFAP45和AK8之间的AMP结合界面。与单独使用ATP相比，在添加AMP或ADP的情况下，Cfap45−/−小鼠的失动力精子的微管滑动得以恢复。我们提出CFAP45通过腺嘌呤核苷酸稳态模块支持哺乳动物纤毛和鞭毛跳动。单磷酸腺苷调节动力蛋白atp酶介导的纤毛和鞭毛跳动的机制尚不清楚。在这里，作者确定了一个轴突模块，包括纤毛和鞭毛相关蛋白45，支持腺嘌呤核苷酸稳态和人类纤毛病的基础
Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45−/− mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module. The mechanism by which adenosine monophosphate modulates dynein ATPase-mediated ciliary and flagellar beating remains obscure. Here the authors identify an axonemal module including cilia and flagella associated protein 45 that supports adenine nucleotide homeostasis and underlies a human ciliopathy
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影响因子：
64.8
作者：
GIBBONS, IR;GIBBONS, BH;ASAI, DJ
通讯作者：
ASAI, DJ
影响因子：
--
作者：
Hayashi, Shuichi;Shingyoji, Chikako
通讯作者：
Shingyoji, Chikako
影响因子：
13.8
作者：
Bhabha G;Johnson GT;Schroeder CM;Vale RD
通讯作者：
Vale RD
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
16.6
作者：
Boldt K;van Reeuwijk J;Lu Q;Koutroumpas K;Nguyen TM;Texier Y;van Beersum SE;Horn N;Willer JR;Mans DA;Dougherty G;Lamers IJ;Coene KL;Arts HH;Betts MJ;Beyer T;Bolat E;Gloeckner CJ;Haidari K;Hetterschijt L;Iaconis D;Jenkins D;Klose F;Knapp B;Latour B;Letteboer SJ;Marcelis CL;Mitic D;Morleo M;Oud MM;Riemersma M;Rix S;Terhal PA;Toedt G;van Dam TJ;de Vrieze E;Wissinger Y;Wu KM;Apic G;Beales PL;Blacque OE;Gibson TJ;Huynen MA;Katsanis N;Kremer H;Omran H;van Wijk E;Wolfrum U;Kepes F;Davis EE;Franco B;Giles RH;Ueffing M;Russell RB;Roepman R;UK10K Rare Diseases Group
通讯作者：
UK10K Rare Diseases Group