5w09
From Proteopedia
Crystal Structure of a twinned Human Activation-induced Cytidine Deaminase catalytic core (1-153) at 2.0A resolution
Structural highlights
Disease[AICDA_HUMAN] Hyper-IgM syndrome type 2. The disease is caused by mutations affecting the gene represented in this entry. Function[AICDA_HUMAN] Single-stranded DNA-specific cytidine deaminase. Involved in somatic hypermutation (SHM), gene conversion, and class-switch recombination (CSR) in B-lymphocytes by deaminating C to U during transcription of Ig-variable (V) and Ig-switch (S) region DNA. Required for several crucial steps of B-cell terminal differentiation necessary for efficient antibody responses (PubMed:18722174, PubMed:21385873, PubMed:21518874, PubMed:27716525). May also play a role in the epigenetic regulation of gene expression by participating in DNA demethylation (PubMed:21496894).[1] [2] [3] [4] [5] Publication Abstract from PubMedThe protein-folding mechanism remains a major puzzle in life science. Purified soluble activation-induced cytidine deaminase (AID) is one of the most difficult proteins to obtain. Starting from inclusion bodies containing a C-terminally truncated version of AID (residues 1-153; AID(153)), an optimized in vitro folding procedure was derived to obtain large amounts of AID(153), which led to crystals with good quality and to final structural determination. Interestingly, it was found that the final refolding yield of the protein is proline residue-dependent. The difference in the distribution of cis and trans configurations of proline residues in the protein after complete denaturation is a major determining factor of the final yield. A point mutation of one of four proline residues to an asparagine led to a near-doubling of the yield of refolded protein after complete denaturation. It was concluded that the driving force behind protein folding could not overcome the cis-to-trans proline isomerization, or vice versa, during the protein-folding process. Furthermore, it was found that successful refolding of proteins optimally occurs at high pH values, which may mimic protein folding in vivo. It was found that high pH values could induce the polarization of peptide bonds, which may trigger the formation of protein secondary structures through hydrogen bonds. It is proposed that a hydrophobic environment coupled with negative charges is essential for protein folding. Combined with our earlier discoveries on protein-unfolding mechanisms, it is proposed that hydrogen bonds are a primary driving force for de novo protein folding. Hydrogen bonds are a primary driving force for de novo protein folding.,Lee S, Wang C, Liu H, Xiong J, Jiji R, Hong X, Yan X, Chen Z, Hammel M, Wang Y, Dai S, Wang J, Jiang C, Zhang G Acta Crystallogr D Struct Biol. 2017 Dec 1;73(Pt 12):955-969. doi:, 10.1107/S2059798317015303. Epub 2017 Nov 10. PMID:29199976[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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