O-fucosylation stabilizes the TSR3 motif in thrombospondin-1 by interacting with nearby amino acids and protecting a disulfide bond

Berardinelli, Steven J.; Eletsky, Alexander; Valero‐González, Jessika; Ito, Atsuko; Manjunath, Rajashri; Hurtado‐Guerrero, R.; Prestegard, James R.; Woods, Robert J.; Haltiwanger, Robert S.

doi:10.1016/j.jbc.2022.102047

Cited by 5 publications

(4 citation statements)

References 66 publications

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“…1 ). This can be interpreted as a quality control mechanism that maintains the folded, disulfide-bonded state of target TSRs, promoting onward trafficking and secretion of the respective protein ( 14 ).…”

Section: Ptms: Roles In the Structure And Function Of Ecm Proteinsmentioning

confidence: 99%

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Passing the post: roles of posttranslational modifications in the form and function of extracellular matrix

Adams

2023

American Journal of Physiology-Cell Physiology

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The extracellular matrix (ECM) is central to the physiology of animal tissues, through its multifaceted roles in tissue structure, mechanical properties and cell interactions, and by its cell-signalling activities that regulate cell phenotype and behaviour. The secretion of ECM proteins typically involves multiple transport and processing steps within the endoplasmic reticulum and the subsequent compartments of the secretory pathway. Many ECM proteins are substituted with various post-translational modifications (PTMs) and there is increasing evidence of how PTM additions are required for ECM protein secretion or functionality within the extracellular milieu. The targeting of PTM-addition steps may thus offer opportunities to manipulate ECM quality or quantity, in vitro or in vivo. This review discusses selected examples of PTMs of ECM proteins for which the PTM has known importance for anterograde trafficking and secretion of the core protein, and/or loss-of-function of the respectively modifying enzyme leads to alterations of ECM structure or function with pathophysiological consequences in humans. Members of the protein disulphide isomerase (PDI) family have central roles in disulphide bond formation and isomerisation within the endoplasmic reticulum, and are discussed in relation to emerging knowledge of the roles of certain PDIs in ECM production in the pathophysiological context of breast cancer. Cumulative data suggest the possible applicability of inhibition of PDIA3 activity to modulate ECM composition and functionality within the tumour microenvironment.

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Section: Ptms: Roles In the Structure And Function Of Ecm Proteinsmentioning

confidence: 99%

“… Posttranslational modifications support stable folding of the TSR domains of thrombospondin-1. The structural model [PDB 7YYK ( 14 )] shows the second (purple) and third (red) TSR domains. Disulfide bonds are in yellow, with cysteines numbered from the N-terminus of the domain.…”

Section: Ptms: Roles In the Structure And Function Of Ecm Proteinsmentioning

confidence: 99%

Passing the post: roles of posttranslational modifications in the form and function of extracellular matrix

Adams

2023

American Journal of Physiology-Cell Physiology

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“…The enzyme Protein O‐fucosyltransferase‐2 (POFUT2) adds O‐fucose to TSP1 in the endoplasmic reticulum, to the consensus sequence C‐X‐X‐S/T‐C, containing the first and second of the conserved cysteines of “group 1” type TSP1 domains, such as found in the CCN proteins. Berardinelli et al found the O‐fucose modification to provide stability to the TSP1 motif through covering the disulfide bond linking strands 2 and 3, protecting it from reduction (Berardinelli et al 2022). O‐fucosylation of the TSP domain is believed to promote secretion of proteins such as extracellular proteases and may be important for interactions with other parts of the protein and other binding partners (Holdener and Haltiwanger 2019).…”

Section: The Tsp1‐domain: Structure and Functionmentioning

confidence: 99%

“…A recent paper by Neupane et al identifies CCN2 as a POFUT2 substrate. O-fucosylation was shown to be essential for remodeling of the ECM and signaling during bone development and thus, this post-translational modification could be important for the protein function through interactions with ligands and binding partners of the ECM (Berardinelli et al 2022). It remains to be investigated how this modulation of the CCN protein TSP1 domain affects their function.…”

Section: The Tsp1-domain: Structure and Functionmentioning

confidence: 99%

Structural insights into regulation of CCN protein activities and functions

Monsen

Attramadal

2023

J. Cell Commun. Signal.

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CCN proteins play important functions during development, in repair mechanisms following tissue injury, as well as in pathophysiologic mechanisms of metastasis of cancer. CCNs are secreted proteins that have a multimodular structure and are categorized as matricellular proteins. Although the prevailing view is that CCN proteins regulate biologic processes by interacting with a wide array of other proteins in the microenvironment of the extracellular matrix, the molecular mechanisms of action of CCN proteins are still poorly understood. Not dissuading the current view, however, the recent appreciation that these proteins are signaling proteins in their own right and may even be considered preproproteins controlled by endopeptidases to release a C-terminal bioactive peptide has opened new avenues of research. Also, the recent resolution of the crystal structure of two of the domains of CCN3 have provided new knowledge with implications for the entire CCN family. These resolved structures in combination with structural predictions based upon the AlphaFold artificial intelligence tool provide means to shed new light on CCN functions in context of the notable literature in the field. CCN proteins have emerged as important therapeutic targets in several disease conditions, and clinical trials are currently ongoing. Thus, a review that critically discusses structure - function relationship of CCN proteins, in particular as it relates to interactions with other proteins in the extracellular milieu and on the cell surface, as well as to cell signaling activities of these proteins, is very timely. Graphical abstract Suggested mechanism for activation and inhibition of signaling by the CCN protein family (graphics generated with BioRender.com).

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Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2021–2022

Harvey

2024

Mass Spectrometry Reviews

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The use of matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry for the analysis of carbohydrates and glycoconjugates is a well‐established technique and this review is the 12th update of the original article published in 1999 and brings coverage of the literature to the end of 2022. As with previous review, this review also includes a few papers that describe methods appropriate to analysis by MALDI, such as sample preparation, even though the ionization method is not MALDI. The review follows the same format as previous reviews. It is divided into three sections: (1) general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation, quantification and the use of computer software for structural identification. (2) Applications to various structural types such as oligo‐ and polysaccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals, and (3) other general areas such as medicine, industrial processes, natural products and glycan synthesis where MALDI is extensively used. Much of the material relating to applications is presented in tabular form. MALDI is still an ideal technique for carbohydrate analysis, particularly in its ability to produce single ions from each analyte and advancements in the technique and range of applications show little sign of diminishing.

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O-fucosylation stabilizes the TSR3 motif in thrombospondin-1 by interacting with nearby amino acids and protecting a disulfide bond

Cited by 5 publications

References 66 publications

Passing the post: roles of posttranslational modifications in the form and function of extracellular matrix

Passing the post: roles of posttranslational modifications in the form and function of extracellular matrix

Structural insights into regulation of CCN protein activities and functions

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2021–2022

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