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To date, a total of nine different mutations including eight truncation mutations and one missense mutation (E343K, CXCR4<jats:sup>E343K<\/jats:sup>) distributed in the C-terminus of CXCR4 have been identified in humans. Studies have clarified that the loss of phosphorylation sites in the C-terminus of truncated CXCR4 impairs the desensitization process, enhances the activation of G-protein, prolongs downstream signaling pathways and introduces over immune responses, thereby causing WHIM syndrome. So far, there is only one reported case of WHIM syndrome with a missense mutation, CXCR4<jats:sup>E343K<\/jats:sup>, which has a full length of C-terminus with entire phosphorylation sites, no change in all potential phosphorylation sites. The mechanism of the missense mutation (CXCR4<jats:sup>E343K<\/jats:sup>) causing WHIM syndrome is unknown. This study aimed to characterize the effect of mutation at the 343 site of CXCR4 causing the replacement of arginine\/E with glutamic acid\/K on the receptor signal transduction, and elucidate the mechanism underling CXCR4<jats:sup>E343K<\/jats:sup> causing WHIM in the reported family.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We completed a series of mutagenesis to generate different mutations at the 343 site of CXCR4 tail, and established a series of HeLa cell lines stably expressing CXCR4<jats:sup>WT<\/jats:sup> or CXCR4<jats:sup>E343D<\/jats:sup> (glutamic acid\/E replaced with aspartic acid\/D) or CXCR4<jats:sup>E343K<\/jats:sup> (glutamic acid\/E replaced with lysine\/K) or CXCR4<jats:sup>E343R<\/jats:sup> (glutamic acid\/E replaced with arginine\/R) or CXCR4<jats:sup>E343A<\/jats:sup> (glutamic acid\/E replaced with alanine\/A) and then systematically analyzed functions of the CXCR4 mutants above. Results showed that the cells overexpressing of CXCR4<jats:sup>E343D<\/jats:sup> had no functional changes with comparison that of wild type CXCR4. However, the cells overexpressing of CXCR4<jats:sup>E343K<\/jats:sup> or CXCR4<jats:sup>E343R<\/jats:sup> or CXCR4<jats:sup>E343A<\/jats:sup> had enhanced cell migration, prolonged the phosphorylation of ERK1\/2, p38, JNK1\/2\/3, aggravated activation of PI3K\/AKT\/NF-\u03baB signal pathway, introduced higher expression of TNFa and IL6, suggesting over immune response occurred in CXCR4 mutants with charge change at the 343 site of receptor tail, as a result, causing WHIM syndrome. Biochemical analysis of those mutations at the 343 site of CXCR4 above shows that CXCR4 mutants with no matter positive or neutral charge have aberrant signal pathways downstream of activated mutated CXCR4, only CXVR4 with negative charge residues at the site shows normal signal pathway post activation with stromal-derived factor (SDF1, also known as CXCL12).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Taken together, our results demonstrated that the negative charge at the 343 site of CXCR4 plays an essential role in regulating the down-stream signal transduction of CXCR4 for physiological events, and residue charge changes, no matter positive or neutral introduce aberrant activities and functions of CXCR4, thus consequently lead to WHIM syndrome.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12860-021-00347-9","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T08:02:59Z","timestamp":1611388979000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The negative charge of the 343 site is essential for maintaining physiological functions of CXCR4"],"prefix":"10.1186","volume":"22","author":[{"given":"Liqing","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuhong","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayab","family":"Tariq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changxin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,23]]},"reference":[{"issue":"4","key":"347_CR1","doi-asserted-by":"publisher","first-page":"317","DOI":"10.2174\/156652411795677963","volume":"11","author":"L Dotta","year":"2011","unstructured":"Dotta L, Tassone L, Badolato R. 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