Connexin: Difference between revisions

← Older edit Newer edit →

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Doaa Naffaa, Safaa Salah Hussiesy, Michal Harel, Jaime Prilusky

@@ Line 12: / Line 12: @@
 ==Phenotypic results of mutations in connexin 26==
-Mutations in human Connexin 26 (hCx26) can lead to [http://en.wikipedia.org/wiki/Congenital_hearing_loss congenital hearing loss] (uptodate reference PMID 25153233)<ref>pmid 25153233</ref> (1 child per 1000 frequency) that can be syndromic or non-syndromic. Non-syndromic hearing loss (NSHL) is characterized by sensorineural hearing loss in the absence of other symptoms, while syndromic hearing loss affects other organ systems, primarily the skin.  mutations in GJB2 (the gene that encodes for Cx26) account for about half of all congenital and autosomal recessive nonsyndromic hearing loss in every population tested . Although the most frequently occurring (NSHL) mutations produce severely truncated proteins due to frameshift or missense, almost 80% of the known deafness mutations are actually single amino acid changes or deletions. These mutations have been found across the entire sequence of Cx26. The majority of NSHL mutations cause either generalized folding problems that result in the failure of Cx26 to traffic to the cell surface, or are permissive for the formation of gap junction plaques, but prevent intercellular channel function.<ref name='mutant int'>pmid 23967136</ref>
+Mutations in human Connexin 26 (hCx26) can lead to [http://en.wikipedia.org/wiki/Congenital_hearing_loss congenital hearing loss] <ref>pmid 25153233</ref> (1 child per 1000 frequency) that can be syndromic or non-syndromic. Non-syndromic hearing loss (NSHL) is characterized by sensorineural hearing loss in the absence of other symptoms, while syndromic hearing loss affects other organ systems, primarily the skin.  mutations in GJB2 (the gene that encodes for Cx26) account for about half of all congenital and autosomal recessive nonsyndromic hearing loss in every population tested . Although the most frequently occurring (NSHL) mutations produce severely truncated proteins due to frameshift or missense, almost 80% of the known deafness mutations are actually single amino acid changes or deletions. These mutations have been found across the entire sequence of Cx26. The majority of NSHL mutations cause either generalized folding problems that result in the failure of Cx26 to traffic to the cell surface, or are permissive for the formation of gap junction plaques, but prevent intercellular channel function.<ref name='mutant int'>pmid 23967136</ref>
@@ Line 38: / Line 38: @@
 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'/>
-Two structural crystallographic studies have been commenced on Cx26, the first one describing the WT protein in a resolution of 3.5 Å by Tsuhikara, T. (2009),(PMID 19622859)<ref name='Structure'/>,  and the second  one deals with two types of mutations in the N terminus of the protein by Fujiyoshi, Y. (2011),(PMID 21094651).<ref name='pdb'/>
+Two structural crystallographic studies have been commenced on Cx26, the first one describing the WT protein in a resolution of 3.5 Å by Tsuhikara, T.(2009)<ref name='Structure'/>, and the second one deals with two types of mutations in the N terminus of the protein by Fujiyoshi, Y.(2011).<ref name='pdb'/>
 Gap junction channels are unique in that they possess multiple mechanisms for channel closure, several of which involve the <scene name='70/701426/N_terminal/1'>N terminus</scene> (blue coloured) as a key component in gating, and possibly assembly. <ref name='pdb'>pmid 21094651</ref>
 The 3D structure of a mutant human connexin 26 <scene name='70/701426/Mutant_connexin26_-cx26m34a/1'>(Cx26M34A)</scene> channel shows an unexpected density within the vestibule of each hemichannel compared to the <scene name='70/701426/Wild_type_connexin/1'>wild type connexin 26</scene> , which is called a plug <ref name='pdb'/> , That plug was decreased in the the human mutant connexin 26 <scene name='70/701426/Deletion/1'>Cx26del2-7</scene> structure, indicating that the N terminus significantly contributes to form this plug feature. Experiments with this mutant show significantly reduced dye coupling between [http://en.wikipedia.org/wiki/HeLa HeLa cells] transiently expressing Cx26M34A gap junctions. <ref name='pdb'/>