Structural highlights
Disease
SAS6_HUMAN Autosomal recessive primary microcephaly. The disease is caused by variants affecting the gene represented in this entry.
Function
SAS6_HUMAN Central scaffolding component of the centrioles ensuring their 9-fold symmetry. Required for centrosome biogenesis and duplication: required both for mother-centriole-dependent centriole duplication and deuterosome-dependent centriole amplification in multiciliated cells. Overexpression results in excess foci-bearing centriolar markers. Required for the recruitment of STIL to the procentriole and for STIL-mediated centriole amplification (PubMed:22020124).[1] [2] [3] [4]
Publication Abstract from PubMed
Centrioles are key eukaryotic organelles that are responsible for the formation of cilia and flagella, and for organizing the microtubule network and the mitotic spindle in animals. Centriole assembly requires oligomerization of the essential protein spindle assembly abnormal 6 (SAS-6), which forms a structural scaffold templating the organization of further organelle components. A dimerization interaction between SAS-6 N-terminal "head" domains was previously shown to be essential for protein oligomerization in vitro and for function in centriole assembly. Here, we developed a pharmacophore model allowing us to assemble a library of low-molecular-weight ligands predicted to bind the SAS-6 head domain and inhibit protein oligomerization. We demonstrate using NMR spectroscopy that a ligand from this family binds at the head domain dimerization site of algae, nematode, and human SAS-6 variants, but also that another ligand specifically recognizes human SAS-6. Atomistic molecular dynamics simulations starting from SAS-6 head domain crystallographic structures, including that of the human head domain which we now resolve, suggest that ligand specificity derives from favorable Van der Waals interactions with a hydrophobic cavity at the dimerization site.
Identification of compounds that bind the centriolar protein SAS-6 and inhibit its oligomerization.,Busch JMC, Matsoukas MT, Musgaard M, Spyroulias GA, Biggin PC, Vakonakis I J Biol Chem. 2020 Dec 25;295(52):17922-17934. doi: 10.1074/jbc.RA120.014780. Epub , 2020 Sep 1. PMID:32873708[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Leidel S, Delattre M, Cerutti L, Baumer K, Gonczy P. SAS-6 defines a protein family required for centrosome duplication in C. elegans and in human cells. Nat Cell Biol. 2005 Feb;7(2):115-25. PMID:15665853 doi:ncb1220
- ↑ Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol. 2005 Nov;7(11):1140-6. PMID:16244668 doi:http://dx.doi.org/10.1038/ncb1320
- ↑ Kleylein-Sohn J, Westendorf J, Le Clech M, Habedanck R, Stierhof YD, Nigg EA. Plk4-induced centriole biogenesis in human cells. Dev Cell. 2007 Aug;13(2):190-202. PMID:17681131 doi:http://dx.doi.org/10.1016/j.devcel.2007.07.002
- ↑ Tang CJ, Lin SY, Hsu WB, Lin YN, Wu CT, Lin YC, Chang CW, Wu KS, Tang TK. The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation. EMBO J. 2011 Oct 21;30(23):4790-804. doi: 10.1038/emboj.2011.378. PMID:22020124 doi:http://dx.doi.org/10.1038/emboj.2011.378
- ↑ Busch JMC, Matsoukas MT, Musgaard M, Spyroulias GA, Biggin PC, Vakonakis I. Identification of compounds that bind the centriolar protein SAS-6 and inhibit its oligomerization. J Biol Chem. 2020 Dec 25;295(52):17922-17934. PMID:32873708 doi:10.1074/jbc.RA120.014780
