Journal:Acta Cryst F:S2053230X20010122
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[[Image:Tabg.png|thumb|350px|left|Sequence alignment of LRRs in TMK3. The boundary of each LRR is shown on its right. The conserved residues are shown with yellow background. The solid black star indicates the amino acids specific to plant LRR proteins.]] | [[Image:Tabg.png|thumb|350px|left|Sequence alignment of LRRs in TMK3. The boundary of each LRR is shown on its right. The conserved residues are shown with yellow background. The solid black star indicates the amino acids specific to plant LRR proteins.]] | ||
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| - | The non-LRR has a Cys cluster with the pattern of ''Cx''<sub>''6-7''</sub>''Cx''<sub>''29-30''</sub>''Cx''<sub>''6-11''</sub>''C'' (Cys315-Cys323 and Cys353-Cys361) and a conserved motif of Lx8Yx7-8WxG (Figure 2) similar to Yx8KG found in many LRR- receptor-like kinases (Fritz-Laylin ''et al.,'' 2005<ref name="Fritz">PMID:15955925</ref>). Most of LRR structures have caps, which shield the hydrophobic core of the first LRR unit at the N-terminus and the last unit at the C-terminus. In extracellular proteins or extracellular regions, the N-terminal and C-terminal caps frequently consist of Cys clusters including two or four Cys residues. The Cys clusters on the N- terminal and C-terminal sides of the LRR arcs are called LRRNT and LRRCT, respectively. Almost all known typical LRR structures include an LRRNT, some of which also have an LRRCT. TMK3-LRR belongs to the LRR subgroups that lacks LRRCT and possesses only an LRRNT (with Cx6C) characterized by a disulfide bond between Cys54 and Cys61. We have also observed five asparagine residues (N165, N170, N223, N286 and N448) modified by N-glycosylation (Figure 3C). | + | The non-LRR has a Cys cluster with the pattern of ''Cx''<sub>''6-7''</sub>''Cx''<sub>''29-30''</sub>''Cx''<sub>''6-11''</sub>''C'' (Cys315-Cys323 and Cys353-Cys361) and a conserved motif of Lx8Yx7-8WxG (Figure 2) similar to Yx8KG found in many LRR- receptor-like kinases (Fritz-Laylin ''et al.,'' 2005<ref name="Fritz">PMID:15955925</ref>). |
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| + | [[Image:Fig2qw.tif|thumb|350px|left|]] | ||
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| + | Most of LRR structures have caps, which shield the hydrophobic core of the first LRR unit at the N-terminus and the last unit at the C-terminus. In extracellular proteins or extracellular regions, the N-terminal and C-terminal caps frequently consist of Cys clusters including two or four Cys residues. The Cys clusters on the N- terminal and C-terminal sides of the LRR arcs are called LRRNT and LRRCT, respectively. Almost all known typical LRR structures include an LRRNT, some of which also have an LRRCT. TMK3-LRR belongs to the LRR subgroups that lacks LRRCT and possesses only an LRRNT (with Cx6C) characterized by a disulfide bond between Cys54 and Cys61. We have also observed five asparagine residues (N165, N170, N223, N286 and N448) modified by N-glycosylation (Figure 3C). | ||
The physiological function of TMK3-ECD is not clearly understood due to the lack of information on the correlation between function and structure. The non-LRR might contribute to ligand interactions (Matsushima ''et al.,'' 2009<ref name="Matsushima">PMID:19580846</ref>; Matsushima & Miyashita, 2012<ref name="Matsushima1">PMID:24970139</ref>). Based on circular dichroism data, Afzal and Lightfoot (Afzal and Lightfoot, 2007<ref name="Afzal">PMID:17287130</ref>) suggested that non-LRR may provide binding diversity to the domains and participate in ligand/protein interactions, dimerization or both. The TMK3-ECD structure revealed a significant electronegative groove located at the non-LRR region between the two LRR domains (Figure 3D). This suggests that the non-LRR region is likely a ligand binding pocket that can accommodate positively charged ligands, such as peptides with basic side chains or other electropositive signaling molecules. In addition, the disulfide bonds that stabilize and orient the fold of non-LRR region in TMK3-LRR could be essential for functionality. The disulfide bond between Cys353 to Cys361 is conserved with classical N-cap structure, suggesting its function as an N-cap to stabilize the structure of C-LRR. The other disulfide bond (Cys315-Cys323) is responsible for connecting two LRR domains. Breaking this pairs of disulfide bond may cause the two LRR domains to be converted into one, altering the ligand binding interaction. Besides, it may also play a critical role in a changing redox environment. The number of N-LRR is greater than the number of C-LRR, which brings close proximity of the non-LRR to interact with ligand and the transmembrane region. It also might facilitate signaling in the cytoplasm through interactions with ligand. We also speculate it's possible to have a role for the N- LRR and C-LRR domains that provides more than one scaffold for protein interaction or ligand recognition. | The physiological function of TMK3-ECD is not clearly understood due to the lack of information on the correlation between function and structure. The non-LRR might contribute to ligand interactions (Matsushima ''et al.,'' 2009<ref name="Matsushima">PMID:19580846</ref>; Matsushima & Miyashita, 2012<ref name="Matsushima1">PMID:24970139</ref>). Based on circular dichroism data, Afzal and Lightfoot (Afzal and Lightfoot, 2007<ref name="Afzal">PMID:17287130</ref>) suggested that non-LRR may provide binding diversity to the domains and participate in ligand/protein interactions, dimerization or both. The TMK3-ECD structure revealed a significant electronegative groove located at the non-LRR region between the two LRR domains (Figure 3D). This suggests that the non-LRR region is likely a ligand binding pocket that can accommodate positively charged ligands, such as peptides with basic side chains or other electropositive signaling molecules. In addition, the disulfide bonds that stabilize and orient the fold of non-LRR region in TMK3-LRR could be essential for functionality. The disulfide bond between Cys353 to Cys361 is conserved with classical N-cap structure, suggesting its function as an N-cap to stabilize the structure of C-LRR. The other disulfide bond (Cys315-Cys323) is responsible for connecting two LRR domains. Breaking this pairs of disulfide bond may cause the two LRR domains to be converted into one, altering the ligand binding interaction. Besides, it may also play a critical role in a changing redox environment. The number of N-LRR is greater than the number of C-LRR, which brings close proximity of the non-LRR to interact with ligand and the transmembrane region. It also might facilitate signaling in the cytoplasm through interactions with ligand. We also speculate it's possible to have a role for the N- LRR and C-LRR domains that provides more than one scaffold for protein interaction or ligand recognition. | ||
Revision as of 13:10, 4 August 2020
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