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941.
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943.
Erik Procko Rickard Hedman Keith Hamilton Jayaraman Seetharaman Sarel J. Fleishman Min Su James Aramini Gregory Kornhaber John F. Hunt Liang Tong Gaetano T. Montelione David Baker 《Journal of molecular biology》2013
While there has been considerable progress in designing protein–protein interactions, the design of proteins that bind polar surfaces is an unmet challenge. We describe the computational design of a protein that binds the acidic active site of hen egg lysozyme and inhibits the enzyme. The design process starts with two polar amino acids that fit deep into the enzyme active site, identifies a protein scaffold that supports these residues and is complementary in shape to the lysozyme active-site region, and finally optimizes the surrounding contact surface for high-affinity binding. Following affinity maturation, a protein designed using this method bound lysozyme with low nanomolar affinity, and a combination of NMR studies, crystallography, and knockout mutagenesis confirmed the designed binding surface and orientation. Saturation mutagenesis with selection and deep sequencing demonstrated that specific designed interactions extending well beyond the centrally grafted polar residues are critical for high-affinity binding. 相似文献
944.
Yi-Quan Tang Ping Liang Jingheng Zhou Yanxin Lu Lei Lei Xiling Bian KeWei Wang 《The Journal of biological chemistry》2013,288(21):14727-14741
In the brain and heart, auxiliary Kv channel-interacting proteins (KChIPs) co-assemble with pore-forming Kv4 α-subunits to form a native K+ channel complex and regulate the expression and gating properties of Kv4 currents. Among the KChIP1–4 members, KChIP4a exhibits a unique N terminus that is known to suppress Kv4 function, but the underlying mechanism of Kv4 inhibition remains unknown. Using a combination of confocal imaging, surface biotinylation, and electrophysiological recordings, we identified a novel endoplasmic reticulum (ER) retention motif, consisting of six hydrophobic and aliphatic residues, 12–17 (LIVIVL), within the KChIP4a N-terminal KID, that functions to reduce surface expression of Kv4-KChIP complexes. This ER retention capacity is transferable and depends on its flanking location. In addition, adjacent to the ER retention motif, the residues 19–21 (VKL motif) directly promote closed-state inactivation of Kv4.3, thus leading to an inhibition of channel current. Taken together, our findings demonstrate that KChIP4a suppresses A-type Kv4 current via ER retention and enhancement of Kv4 closed-state inactivation. 相似文献
945.
Mingsong Kang Ya-Ping Ko Xiaowen Liang Caná L. Ross Qing Liu Barbara E. Murray Magnus H??k 《The Journal of biological chemistry》2013,288(28):20520-20531
Members of a family of collagen-binding microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) from Gram-positive bacteria are established virulence factors in several infectious diseases models. Here, we report that these adhesins also can bind C1q and act as inhibitors of the classical complement pathway. Molecular analyses of Cna from Staphylococcus aureus suggested that this prototype MSCRAMM bound to the collagenous domain of C1q and interfered with the interactions of C1r with C1q. As a result, C1r2C1s2 was displaced from C1q, and the C1 complex was deactivated. This novel function of the Cna-like MSCRAMMs represents a potential immune evasion strategy that could be used by numerous Gram-positive pathogens. 相似文献
946.
Yuan Liu Zhi-chun Zhang Shu-wen Qian You-you Zhang Hai-yan Huang Yan Tang Liang Guo Xi Li Qi-Qun Tang 《The Journal of biological chemistry》2013,288(12):8222-8230
BMP4 has been shown to induce C3H10T1/2 pluripotent stem cells to commit to adipocyte lineage. In addition to several proteins identified, microRNAs also play a critical role in the process. In this study, we identified microRNA-140 (miR-140) as a direct downstream component of the BMP4 signaling pathway during the commitment of C3H10T1/2 cells to adipocyte lineage. Overexpression of miR-140 in C3H10T1/2 cells promoted commitment, whereas knockdown of its expression led to impairment. Additional studies indicated that Ostm1 is a bona fide target of miR-140, which is significantly decreased during commitment, and Ostm1 was also demonstrated to function as an anti-adipogenic factor. 相似文献
947.
Debarati Basu Yan Liang Xiao Liu Klaus Himmeldirk Ahmed Faik Marcia Kieliszewski Michael Held Allan M. Showalter 《The Journal of biological chemistry》2013,288(14):10132-10143
Although plants contain substantial amounts of arabinogalactan proteins (AGPs), the enzymes responsible for AGP glycosylation are largely unknown. Bioinformatics indicated that AGP galactosyltransferases (GALTs) are members of the carbohydrate-active enzyme glycosyltransferase (GT) 31 family (CAZy GT31) involved in N- and O-glycosylation. Six Arabidopsis GT31 members were expressed in Pichia pastoris and tested for enzyme activity. The At4g21060 gene (named AtGALT2) was found to encode activity for adding galactose (Gal) to hydroxyproline (Hyp) in AGP protein backbones. AtGALT2 specifically catalyzed incorporation of [14C]Gal from UDP-[14C]Gal to Hyp of model substrate acceptors having AGP peptide sequences, consisting of non-contiguous Hyp residues, such as (Ala-Hyp) repetitive units exemplified by chemically synthesized (AO)7 and anhydrous hydrogen fluoride-deglycosylated d(AO)51. Microsomal preparations from Pichia cells expressing AtGALT2 incorporated [14C]Gal to (AO)7, and the resulting product co-eluted with (AO)7 by reverse-phase HPLC. Acid hydrolysis of the [14C]Gal-(AO)7 product released 14C-radiolabel as Gal only. Base hydrolysis of the [14C]Gal-(AO)7 product released a 14C-radiolabeled fragment that co-eluted with a Hyp-Gal standard after high performance anion-exchange chromatography fractionation. AtGALT2 is specific for AGPs because substrates lacking AGP peptide sequences did not act as acceptors. Moreover, AtGALT2 uses only UDP-Gal as the substrate donor and requires Mg2+ or Mn2+ for high activity. Additional support that AtGALT2 encodes an AGP GALT was provided by two allelic AtGALT2 knock-out mutants, which demonstrated lower GALT activities and reductions in β-Yariv-precipitated AGPs compared with wild type plants. Confocal microscopic analysis of fluorescently tagged AtGALT2 in tobacco epidermal cells indicated that AtGALT2 is probably localized in the endomembrane system consistent with its function. 相似文献
948.
949.
Shuai Wu Shui-Di Zheng Hong-Ling Huang Li-Chong Yan Xiao-Fei Yin Hai-Neng Xu Kang-Jian Zhang Jing-Hua Gui Liang Chu Xin-Yuan Liu 《The Journal of biological chemistry》2013,288(49):35500-35510
Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration. 相似文献
950.