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 binding site #2. | 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_2/2'>binding site #2</scene>. | ||
It is clear from the structure that F668 is important in the second binding site because it sits in the hydrophobic pocket of Rab8a created by 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 second binding site because it sits in the <scene name='88/881644/Hydrophobic_pocket/1'>hydrophobic pocket</scene> of Rab8a created by 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"/> | ||
The N591K mutation also causes significant reduction in binding of Rab8a proteins but the reason for this is different than in the case of F668V mutation. This AA is not part of any binding site but it seems to be important in the maintenance of the correct features of the ASH domain which are essential for Rab8a binding. The effect of this mutation was studied in silico and it showed that the mutation causes the ASH domain to alter its flexibility and overall fold. Although the highest change was observed in the AAs that surrounds the N591K mutation, the substitution caused subsequent changes in most parts of the protein which had brought about decreases of prevalence of hydrogen bonds between Rab8a and OCRL1 which led to a lower stability of their interaction.<ref name="com"/> | The N591K mutation also causes significant reduction in binding of Rab8a proteins but the reason for this is different than in the case of F668V mutation. This AA is not part of any binding site but it seems to be important in the maintenance of the correct features of the ASH domain which are essential for Rab8a binding. The effect of this mutation was studied in silico and it showed that the mutation causes the ASH domain to alter its flexibility and overall fold. Although the highest change was observed in the AAs that surrounds the N591K mutation, the substitution caused subsequent changes in most parts of the protein which had brought about decreases of prevalence of hydrogen bonds between Rab8a and OCRL1 which led to a lower stability of their interaction.<ref name="com"/> | ||