Connexin: Difference between revisions
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Of notice, about half of all cases of human pre-lingual recessive deafness in countries surrounding the Mediterranean have been linked to mutations in the GJB2 gene<ref name='important'>pmid 24624091</ref>,<ref name='Structure'>pmid 19622859</ref> | Of notice, about half of all cases of human pre-lingual recessive deafness in countries surrounding the Mediterranean have been linked to mutations in the GJB2 gene<ref name='important'>pmid 24624091</ref>,<ref name='Structure'>pmid 19622859</ref> | ||
*'''Connexin 26''' participates in K+ transport in sensory hair cells in the ear and its mutations are causes of deafness<ref>pmid 9285800</ref> | |||
*'''Connexin 31''' mutations are associated with skin and auditory system disorders<ref>PMID 16549784</ref> | |||
*'''Connexin 32''' is found in the peripheral nervous system and its mutations are associated with Charcot-Marie-Tooth disease<ref>PMID 30042657</ref> | |||
*'''Connexin 36''' regulates the in vivo dynamics of insulin secretion which is important for glucose homeostasis<ref>PMID 22511206</ref> | |||
*'''Connexin 40''' is found in the atrial myocardium and its mutations are associated with trial fibrillation<ref>PMID 19535379</ref> | |||
*'''Connexin 43''' renders glioblastoma resistant to chemotherapy<ref>PMID 35022385</ref> | |||
*'''Connexin 45''' is involved in the maturation of vessel<ref>PMID 10976050</ref> | |||
*'''Connexin 46''' is found in the eye lens and is unregulated in human breast cancer<ref>PMID 32353936</ref> | |||
*'''Connexin 50''' functions as adhesive molecule maintaining lens fibre integrity<ref>PMID 28706245</ref> | |||
[[image:co.jpg | thumb |650px | center | The overall connexon's structure]] <ref>http://en.wikipedia.org/wiki/Connexin</ref> | [[image:co.jpg | thumb |650px | center | The overall connexon's structure]] <ref>http://en.wikipedia.org/wiki/Connexin</ref> | ||
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=Differences between wild type and mutant connexin 26 | ==Differences between wild type and mutant connexin 26== | ||
In general, single site mutations are spread fairly evenly across the whole protein with TM2 having the highest mutation density (number of amino acids with NHLS mutations divided by the total number of amino acids in the domain) at 67% to M1 and E1, having the lowest density of mutations with their respective domains at 33%. According to this criterion, TM4 has a mutation density of 40%. Of the four transmembrane helices, M1, M2 and M3 have attracted the most attention, because of the controversies involved in models with different helix assignments, based on lower resolution cryo-electron crystallographic structures and scanning cysteine accessibility mutagenesis. Far less is known about TM4 and how side chains interact with the other helices and with the lipid bilayer.<ref name='mutant int'/> | In general, single site mutations are spread fairly evenly across the whole protein with TM2 having the highest mutation density (number of amino acids with NHLS mutations divided by the total number of amino acids in the domain) at 67% to M1 and E1, having the lowest density of mutations with their respective domains at 33%. According to this criterion, TM4 has a mutation density of 40%. Of the four transmembrane helices, M1, M2 and M3 have attracted the most attention, because of the controversies involved in models with different helix assignments, based on lower resolution cryo-electron crystallographic structures and scanning cysteine accessibility mutagenesis. Far less is known about TM4 and how side chains interact with the other helices and with the lipid bilayer.<ref name='mutant int'/> | ||
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Functional analysis of the Cx26M34A channels revealed that these channels are predominantly closed, with the residual electrical conductance showing normal voltage gating. N-terminal deletion mutants with and without the M34A mutation showed no electrical activity in paired Xenopus oocytes and significantly decreased dye permeability in HeLa cells. Comparing this closed structure with the published X-ray structure of wild-type Cx26, which is proposed to be in an open state, revealed a radial outward shift in the transmembrane helices in the closed state, presumably to accommodate the N-terminal plug occluding the pore. Because both Cx26del2-7 and Cx26M34Adel2-7 channels are closed, the N terminus appears to have a prominent role in stabilizing the open configuration. <ref name='pdb'/> | Functional analysis of the Cx26M34A channels revealed that these channels are predominantly closed, with the residual electrical conductance showing normal voltage gating. N-terminal deletion mutants with and without the M34A mutation showed no electrical activity in paired Xenopus oocytes and significantly decreased dye permeability in HeLa cells. Comparing this closed structure with the published X-ray structure of wild-type Cx26, which is proposed to be in an open state, revealed a radial outward shift in the transmembrane helices in the closed state, presumably to accommodate the N-terminal plug occluding the pore. Because both Cx26del2-7 and Cx26M34Adel2-7 channels are closed, the N terminus appears to have a prominent role in stabilizing the open configuration. <ref name='pdb'/> | ||
=3D structures of connexin= | |||
[[Connexin 3D structure]] | |||
</StructureSection> | |||
= References = | |||
<references/> | <references/> | ||
[[Category:Topic Page]] | |||