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CFAP45 缺乏通过破坏轴丝腺苷核苷酸动态平衡模块导致 situs 异常和弱精症。

CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module.

机构信息

Department of General Pediatrics, University Hospital Münster, Münster, Germany.

RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.

出版信息

Nat Commun. 2020 Nov 2;11(1):5520. doi: 10.1038/s41467-020-19113-0.

DOI:10.1038/s41467-020-19113-0
PMID:33139725
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7606486/
Abstract

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.

摘要

轴丝动力蛋白 ATP 酶通过三磷酸腺苷 (ATP) 水解来指导纤毛和鞭毛的运动。一磷酸腺苷 (AMP) 和二磷酸腺苷 (ADP) 对鞭毛运动的调节作用尚未完全阐明。在这里，我们描述了人类和小鼠中与纤毛和鞭毛相关的蛋白 45 (CFAP45) 缺乏，表现为总 situs inversus 和弱精症的运动性纤毛病。CFAP45 缺陷的纤毛和鞭毛显示出正常的形态和轴丝超微结构。蛋白质组学分析将 CFAP45 与一个包括动力蛋白 ATP 酶和腺苷酸激酶在内的轴丝模块以及 CFAP52 联系起来，其突变导致类似的纤毛病。CFAP45 在体外与 AMP 结合，结构建模表明 CFAP45 和 AK8 之间存在 AMP 结合界面，这与体外结果一致。与单独使用 ATP 相比，在用 AMP 或 ADP 与 ATP 处理 Cfap45 小鼠的动力异常精子时，微管滑动得到恢复。我们提出 CFAP45 通过一个腺嘌呤核苷酸动态平衡模块来支持哺乳动物的纤毛和鞭毛运动。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/1dd2b8b65f33/41467_2020_19113_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/859915390737/41467_2020_19113_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/e4831844d15b/41467_2020_19113_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/54f2e322e496/41467_2020_19113_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/7dd89436070a/41467_2020_19113_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/4aba9b4ac94d/41467_2020_19113_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/5220ea61a66c/41467_2020_19113_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/1dd2b8b65f33/41467_2020_19113_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/859915390737/41467_2020_19113_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/e4831844d15b/41467_2020_19113_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/54f2e322e496/41467_2020_19113_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/7dd89436070a/41467_2020_19113_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/4aba9b4ac94d/41467_2020_19113_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/5220ea61a66c/41467_2020_19113_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cba/7606486/1dd2b8b65f33/41467_2020_19113_Fig7_HTML.jpg

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[1]
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[7]
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本文引用的文献

[1]
Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia.

Am J Hum Genet. 2019-6-6

[2]
Inner lumen proteins stabilize doublet microtubules in cilia and flagella.

Nat Commun. 2019-3-8

[3]
Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects.

Am J Hum Genet. 2018-11-21

[4]
Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus.

Am J Hum Genet. 2018-11-21

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The flagellar protein Enkurin is required for mouse sperm motility and for transport through the female reproductive tract.

Biol Reprod. 2018-10-1

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Primary ciliary dyskinesia with normal ultrastructure: three-dimensional tomography detects absence of DNAH11.

Eur Respir J. 2018-2-21

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Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways.

Dev Cell. 2017-12-18

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How fast fast-folding proteins fold in silico.

Biochem Biophys Res Commun. 2017-10-7

[9]
A Wnt5 Activity Asymmetry and Intercellular Signaling via PCP Proteins Polarize Node Cells for Left-Right Symmetry Breaking.

Dev Cell. 2017-3-13

[10]
Fine-Tuning Motile Cilia and Flagella: Evolution of the Dynein Motor Proteins from Plants to Humans at High Resolution.

Mol Biol Evol. 2016-12

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