Inositol polyphosphate 5-phosphatase OCRL: Difference between revisions
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Given the important functions of OCRL1 and the amount of its interaction partners it is not surprising that point mutations can cause the serious OCRL. Although, some mutations cause only a mild type of OCRL which is called '''Dent-2 disease'''.<ref name="com">PMID: 31967472</ref> This diseases is caused by different mutations in all domains of OCRL1 just like OCRL.<ref name="china">PMID: 31674016</ref><raf name="com"/><ref name="FH">PMID: 21666675</ref> However, it is characterized solely by heterogeneous kidney malfunctions.<ref name="dent">PMID: 32860533</ref> Even though certain continuum between the two diseases has been suggested it is unclear what causes the different symptoms of various mutations.<ref name="continum">PMID: 21031565</ref> As to the OCRL1 mutations causing OCRL so far only two have been studied closely. It is the substitution of F by V at the position 668 ('''F668V''') and the substitution of N by K at the position 591 ('''N591K''').<ref name="main"/><ref name="com"/> | Given the important functions of OCRL1 and the amount of its interaction partners it is not surprising that point mutations can cause the serious OCRL. Although, some mutations cause only a mild type of OCRL which is called '''Dent-2 disease'''.<ref name="com">PMID: 31967472</ref> This diseases is caused by different mutations in all domains of OCRL1 just like OCRL.<ref name="china">PMID: 31674016</ref><raf name="com"/><ref name="FH">PMID: 21666675</ref> However, it is characterized solely by heterogeneous kidney malfunctions.<ref name="dent">PMID: 32860533</ref> Even though certain continuum between the two diseases has been suggested it is unclear what causes the different symptoms of various mutations.<ref name="continum">PMID: 21031565</ref> As to the OCRL1 mutations causing OCRL so far only two have been studied closely. It is the substitution of F by V at the position 668 ('''F668V''') and the substitution of N by K at the position 591 ('''N591K''').<ref name="main"/><ref name="com"/> | ||
A full crystal structure of the OCRL1 is not known but there are in total 5 structures of different domains which add up together almost the entire protein ([[2kie]], [[2q2v]], [[3qbt]], [[3qis]], [[4cmi]]). What’s more, one crystal structure of partial 5P domain and ASH domain (AA 540-678) in interaction with Rab8a was solved ([[3qbt]]) and shows very well the interaction surface of the proteins. There are two main interaction sites. The first is located in the hinge region (AA 555-559) between ASH domain and 5P domain which is represented by the single 5P domain alpha helix in the crystal structure of 3QBT. The second important binding site is located in beta-strand 9 of the ASH domain (AA 664-670).<ref name="main"/> To see the most important AAs in the binding sites see <scene name='88/881644/Binding_site_1/2'>binding site #1</scene> and <scene name='88/881644/Binding_sites_2/3'>binding site #2</scene>. | A full crystal structure of the OCRL1 is not known but there are in total 5 structures of different domains which add up together almost the entire protein ([[2kie]], [[2q2v]], [[3qbt]], [[3qis]], [[4cmi]]). What’s more, one crystal structure of partial 5P domain and ASH domain (AA 540-678) in interaction with Rab8a was solved ([[3qbt]]) and shows very well the interaction surface of the proteins. There are two main interaction sites. The first is located in the hinge region (AA 555-559) between ASH domain and 5P domain which is represented by the single 5P domain alpha helix in the crystal structure of 3QBT. The second important binding site is located in the beta-strand 9 of the ASH domain (AA 664-670).<ref name="main"/> To see the most important AAs in the binding sites see <scene name='88/881644/Binding_site_1/2'>binding site #1</scene> and <scene name='88/881644/Binding_sites_2/3'>binding site #2</scene>. | ||
It is clear from the structure that F668 is important in the binding site #2 because it sits in the <scene name='88/881644/Hydrophobic_pocket/2'>hydrophobic pocket</scene> of the Rab8a protein created by the I41, G42 and F70. Its substitution by V is therefore a major one since V is smaller and less hydrophobic than F. The mutation then causes disruption of this interaction and reduces the binding ability of OCRL1 with Rab8a by almost 6 folds. Moreover, the mutation causes the protein to be mainly localized in cytoplasm which can significantly hinder its normal function which is connected with vesicular formation.<ref name="main"/> | It is clear from the structure that F668 is important in the binding site #2 because it sits in the <scene name='88/881644/Hydrophobic_pocket/2'>hydrophobic pocket</scene> of the Rab8a protein created by the I41, G42 and F70. Its substitution by V is therefore a major one since V is smaller and less hydrophobic than F. The mutation then causes disruption of this interaction and reduces the binding ability of OCRL1 with Rab8a by almost 6 folds. Moreover, the mutation causes the protein to be mainly localized in cytoplasm which can significantly hinder its normal function which is connected with vesicular formation.<ref name="main"/> | ||