Inositol polyphosphate 5-phosphatase OCRL: Difference between revisions
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== Oculocerebrorenal syndrome of Lowe == | == Oculocerebrorenal syndrome of Lowe == | ||
'''Lowe syndrome''', formally called oculocerebrorenal syndrome, oculocerebrorenal syndrome of Lowe or '''OCRL''', is an '''X-linked multisystemic disorder''' mainly affecting eyes, nervous system (both the central and the peripheral) and kidneys and it is caused by '''mutations in OCRL1 protein'''. The syndrome is rare, its prevalence is 1 in 500 000 in the general population (based on the observations of the American Lowe Syndrome Association and the Italian Association of Lowe syndrome). Almost all of the patients are male. The syndrome is believed to occur worldwide as there are documented cases in America, Europe, Australia, Japan and India.<ref name="Lowe syndrome">PMID: 20301653</ref><ref name="Oculocerebrorenal">PMID: 27011217</ref> | '''Lowe syndrome''', formally called '''oculocerebrorenal syndrome''', oculocerebrorenal syndrome of Lowe or '''OCRL''', is an '''X-linked multisystemic disorder''' mainly affecting eyes, nervous system (both the central and the peripheral) and kidneys and it is caused by '''mutations in OCRL1 protein'''. The syndrome is rare, its prevalence is 1 in 500 000 in the general population (based on the observations of the American Lowe Syndrome Association and the Italian Association of Lowe syndrome). Almost all of the patients are male. The syndrome is believed to occur worldwide as there are documented cases in America, Europe, Australia, Japan and India.<ref name="Lowe syndrome">PMID: 20301653</ref><ref name="Oculocerebrorenal">PMID: 27011217</ref> | ||
There is a rather wide range of different phenotypes in Lowe syndrome patients so the individual cases may vary significantly. Amongst the hallmarks of Lowe syndrome are dense congenital cataracts, some degree of intellectual impairment and usually severe mental retardation, severe growth retardation and generalized hypotonia, proximal renal tubular dysfunction of the renal Fanconi type, which slowly progresses towards renal failure/end-stage renal disease (ERSD) in adulthood.<ref name="Lowe syndrome"/><ref name="Oculocerebrorenal"/> | There is a rather wide range of different phenotypes in Lowe syndrome patients so the individual cases may vary significantly. Amongst the hallmarks of Lowe syndrome are dense congenital cataracts, some degree of intellectual impairment and usually severe mental retardation, severe growth retardation and generalized hypotonia, proximal renal tubular dysfunction of the renal Fanconi type, which slowly progresses towards renal failure/end-stage renal disease (ERSD) in adulthood.<ref name="Lowe syndrome"/><ref name="Oculocerebrorenal"/> | ||
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== OCRL1 == | == OCRL1 == | ||
=== Domains === | === Domains === | ||
The 901 amino acid long OCRL1 is composed of multiple domains which enable it to interact with various partners. OCRL1 consists of an N-terminus '''pleckstrin homology (PH)''' domain without a basic patch required for phosphoinositide recognition and binding. On the other hand, it contains a loop outside of the domain fold that is involved in OCRL1 recruitment to endocytic clathrin-coated pits. <ref name="PH">PMID: 19536138</ref> | The 901 amino acid long '''OCRL1''' or '''Lowe oculocerebronal syndrome protein''' or '''Inositol polyphosphate 5-phosphatase OCRL''' is composed of multiple domains which enable it to interact with various partners. OCRL1 consists of an N-terminus '''pleckstrin homology (PH)''' domain without a basic patch required for phosphoinositide recognition and binding. On the other hand, it contains a loop outside of the domain fold that is involved in OCRL1 recruitment to endocytic clathrin-coated pits. <ref name="PH">PMID: 19536138</ref> | ||
PH domain is followed by one of the major conserved domains of OCRL1 which is a central '''5-phosphatase (5P) domain''', in which two characteristic motifs are present (WXGDXN(F/Y)R and P(A/S)W(C/T)DRIL separated by 60-75 amino acids (AAs)). These play an important role in both substrate binding and catalysis.<ref name="OCRL">PMID: 16101675</ref> This domain has a Dnase I-like fold. <ref name="IP5">PMID: 22381590</ref> | PH domain is followed by one of the major conserved domains of OCRL1 which is a central '''5-phosphatase (5P) domain''', in which two characteristic motifs are present (WXGDXN(F/Y)R and P(A/S)W(C/T)DRIL separated by 60-75 amino acids (AAs)). These play an important role in both substrate binding and catalysis.<ref name="OCRL">PMID: 16101675</ref> This domain has a Dnase I-like fold. <ref name="IP5">PMID: 22381590</ref> | ||
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== Mutations in OCRL1 == | == Mutations in OCRL1 == | ||
<Structure load='3QBT' size='350' frame='true' align='right' caption='Structure of partial 5P domain and ASH domain of OCRL1 (pink) interacting with Rab8a (light blue). ' scene='' /> | <Structure load='3QBT' size='350' frame='true' align='right' caption='Structure of partial 5P domain and ASH domain of OCRL1 (pink) interacting with Rab8a (light blue) complex with GNP, Mg+2 (purple) and sulfate (PDB code [[3qbt]]). ' scene='' /> | ||
Given the important functions of OCRL1 and the amount of its interaction partners it is not surprising that point mutations can cause a 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><ref name="com"/><ref name="FH">PMID: 21666675</ref> However, it is characterized merely 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 a 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><ref name="com"/><ref name="FH">PMID: 21666675</ref> However, it is characterized merely 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"/> | ||
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The N591K mutation also causes significant reduction in binding of Rab8a protein 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 the Rab8a binding. The effect of this mutation was studied in silico and the study showed that the mutation caused the ASH domain to alter its flexibility and overall fold. Although the most significant change was observed in the AAs that surrounded the N591K mutation, the substitution caused subsequent changes in most parts of the protein which 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 protein 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 the Rab8a binding. The effect of this mutation was studied in silico and the study showed that the mutation caused the ASH domain to alter its flexibility and overall fold. Although the most significant change was observed in the AAs that surrounded the N591K mutation, the substitution caused subsequent changes in most parts of the protein which brought about decreases of prevalence of hydrogen bonds between Rab8a and OCRL1 which led to a lower stability of their interaction.<ref name="com"/> | ||
==Inositol polyphosphate 5-phosphatase 3D structures== | |||
[[3D structures of inositol polyphosphate 5-phosphatase OCRL]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
[[Category:Topic Page]] | |||