Edited by Beat ImhofKeywords: Chemokine CXCL14 CXCL12 CXCR4 a b s t r a c t Activation of the CXCL12-CXCR4 pathway is crucial for the migration of hematopoietic stem cells, various immune cells, and malignant tumor cells. Here, we show that another CXC chemokine, CXCL14, specifically binds to CXCR4 with high affinity and inhibits the CXCL12-mediated chemotaxis of human leukemia-derived cell lines and CD34 + hematopoietic progenitor cells. Thus, CXCL14 functions as a natural inhibitor of CXCL12. Our observations suggest that CXCL14 represents, along with CXCR7, molecules that co-evolved with the CXCL12-CXCR4 axis to modulate important physiological processes in development, stem cell maintenance, and immune responses. Structured summary of protein interactions:CXCR4 physically interacts with CXCL14 anti bait coimmunoprecipitation by (View interaction).
Native chemical ligation (NCL) has shown great utility in protein chemistry and has yielded impressive success in the preparation of a wide variety of proteins.[1] This methodology requires peptide thioesters that serve as chemoselective acylating agents for N-terminal cysteinyl peptides to afford ligated peptides through a sequence of reactions consisting of S-S and S-N acyl transfers. The susceptibility of the thioester moiety to basic reagents has necessitated the preparation of the key intermediate by Boc-based solid-phase peptide synthesis (Boc-SPPS) without requiring a nucleophile-mediated deprotection procedure.[2] However, the preferred use of Fmoc-based SPPS with piperidine treatment demands the development of a synthetic methodology using peptide thioesters that are compatible with Fmoc chemistry.In this context, many research groups, including ours, have explored an Fmoc-based synthetic protocol for thioesters. [3][4][5] Among the reported studies, N-S acyl-transfer-mediated procedures have great potential in Fmoc chemistry.[5] We have also developed an N-sulfanylethylaniline linker that can be used for the acyl-transfer-mediated synthesis of peptide thioesters.[5g]Standard Fmoc-SPPS on the sulfanylethylaniline linker followed by N-S acyl transfer under acidic conditions (4 m HCl in DMF) efficiently yielded peptide thioesters (Scheme 1). On the basis of these experimental results, we attempted to utilize an N-terminal cysteinyl N-sulfanylethylanilide (SEAlide) peptide as the middle fragment(s) for sequential NCL, which features the use of more than one thioester fragment.[6] Here, involvement of the SEAlide peptide in the first NCL with a peptide thioester would seem to selectively afford the corresponding ligated SEAlide peptide, which can be used in the second NCL step after conversion of the anilide moiety to the thioester under acidic conditions. The first NCL doubtlessly proceeded; however, contrary to our expectations, a not insignificant amount of cyclic material resulting from the unanticipated intramolecular NCL of the cysteinyl SEAlide peptide was observed (Scheme 2). This unexpected result indicated that the SEAlide moiety could work as a thioester in the presence of an N-terminal cysteinyl residue even under neutral NCL conditions to afford the corresponding NCL product. [7] In this study, we first examined the feasibility of the SEAlide peptide as a crypto-thioester peptide, and discuss the utility of the cryptic thioester in a kinetically controlled NCL. [8] Initial evaluation of the utility of the SEAlide peptide under NCL conditions was attempted through model coupling reactions between peptide 1 and 2 (Table 1). After preliminary experiments, we first fixed the control coupling conditions (1 mm each peptide in 6 m guanidine·HCl (Gn·HCl)-0.2 m sodium phosphate in the presence of 100 mm (4-carboxymethyl)thiophenol (MPAA) [9,10] and 40 mm tris(2-carboxyethyl)phosphine (TCEP), pH 7.3, 37 8C). Under standard conditions, the attempted NCL between 1 a and 2 was almost complete in 48 h and ...
Background:The N-terminal fragment of amyloidogenic apoA-I mutants deposits as fibrils by unknown mechanisms. Results: The G26R mutation partially prevents helix formation of the N-terminal fragment upon lipid binding, thereby facilitating -transition and fibril formation. Conclusion: Membrane binding modulates fibril formation of apoA-I through partially destabilized helical conformation. Significance: The results reveal a new pathway for amyloid fibril formation by apoA-I.
By exploiting a uniquely reactive lysine residue (Lys99) for site-specific attachment of small molecules, the humanized catalytic antibody h38C2 has been used as bioconjugation module in the assembly of chemically programmed antibodies and antibody−drug conjugates. Treatment of h38C2 with β-lactam-functionalized small molecules has been previously shown to result in covalent conjugation by selective formation of a stable amide bond with the ε-amino group of the Lys99 residue. Here we report that heteroaryl methylsulfonyl (MS-PODA)-functionalized small molecules represent an alternative bioconjugation strategy through highly efficient, site-specific, and stable arylation of the Lys99 residue. A set of chemically programmed antibodies and antibody−drug conjugates assembled by Lys99 arylation provided proof-of-concept for the therapeutic utility of this alternative bioconjugation strategy. While being equally effective as β-lactam-functionalized ligands for bioconjugation with catalytic antibody h38C2, the MS-PODA moiety offers distinct synthetic advantages, making it highly attractive.
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