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Mitochondrial Dysfunction and Barth Syndrome
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Arianna F. Anzmann, Steven M. Claypool, Hilary Vernon
Investigations of different yeast lines, representing 21 distinct and conserved human TAZ pathogenic variants, have established seven functional classes of TAZ genetic variation. The first and the largest class, includes variants that result in the production of little to no functional TAZ. The remaining classes include; (2) Mitochondrial mislocalization and aggregate prone; (3) Impaired macromolecular assembly; (4) Catalytically null; (5) Hypomorphs with residual transacylase activity; (6) Degradation due to impaired folding and assembly; and (7) Temperature sensitive71,72. Distinct loss of function (LOF) classes with potential for residual TAZ function suggest a possible genotype-phenotype correlation; however, prior clinical phenotyping studies have not identified such a relationship71,72.
Extending the capabilities of intact-mass analyses to monoclonal immunoglobulins of the E-isotype (IgE)
Published in mAbs, 2022
Wenhua Yang, Daniil G. Ivanov, Igor A. Kaltashov
Above and beyond facilitating intact-mass analysis of the monoclonal IgE and impurities, LCR readily enables meaningful interpretation of native MS studies targeting interaction of this antibody with its antigen (Figures 4–5). Native MS has been steadily gaining popularity in many areas of macromolecular assembly analysis,41 including studies of antibody/antigen interactions7,45,46 (although all such studies were focused on antigen binding by IgG molecules or their fragments). Antibodies of other isotypes exhibit notably higher levels of glycosylation, making applications of native MS to such systems extremely challenging. The approach presented here allows common MS instrumentation to be used for detection and characterization of intact the IgE/antigen complexes despite their high mass and the extreme degree of structural heterogeneity exhibited by the antibody (with the total carbohydrate content accounting for ca. 17% of the protein mass). The ability to observe and quantify intact immune complexes formed by IgE antibodies provides an important dimension in their characterization, which is complementary to the local structural information that can be obtained by fragmenting highly heterogeneous antibodies in solution47,48 or in the gas phase.49,50 Until recently, electron microscopy remained the only means of direct detection and stoichiometry analysis for intact complexes containing IgE molecules,51 but the data interpretation (based on the negative stain image analysis) was not straightforward.
The phosphoinositide code is read by a plethora of protein domains
Published in Expert Review of Proteomics, 2021
Michael Overduin, Troy A. Kervin
Membranes are read by protein domains that selectively bind the lipids that uniquely mark each subcellular organelle and plasma membrane compartment. These conserved domains mediate reversible attachment of proteins to membranes in order to facilitate the assembly and disassembly of signaling and trafficking complexes in response to changes in lipid concentration and locality. The best characterized are the FYVE, PH, and PX domain superfamilies, which exemplify the PI code that controls eukaryotic membrane recognition [1–3]. This overview of the literature reveals a growing array of soluble, folded domains, which are known to recognize various PI lipids and thus localize and mediate signaling, macromolecular assembly, and trafficking functions on most eukaryotic membrane-bound compartments (Table 1).
Clostridioides difficile: innovations in target discovery and potential for therapeutic success
Published in Expert Opinion on Therapeutic Targets, 2021
Tanya M Monaghan, Anna M Seekatz, Benjamin H Mullish, Claudia C. E. R Moore-Gillon, Lisa F. Dawson, Ammar Ahmed, Dina Kao, Weng C Chan
In addition to the large clostridial toxins TcdA and TcdB, a third C. difficile binary toxin (CDT) is associated with the most serious outbreaks of drug-resistance CDI. However, no therapeutic targeting strategies for CDT have been FDA-approved. New research has begun to elucidate the structure of the cell-binding component of CDT (CDTb), revealing a di-heptamer macromolecular assembly, and represents a starting point for developing structure-based drug-design strategies to target C. difficile [77].