Core-glycosylated Mucin-like Repeats from MUC1 Are an Apical Targeting Signal

Kinlough, Carol L.; Poland, Paul A.; Gendler, Sandra J.; Mattila, Polly E.; Mo, Di; Weisz, Ora A.; Hughey, Rebecca P.

doi:10.1074/jbc.m111.289504

Cited by 39 publications

(41 citation statements)

References 42 publications

(62 reference statements)

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“…Glycosylation density could easily be controlled by stoichiometric addition of other amino acid NCAs. For initial trials, we chose to blend in L-Ala NCA, or protected L-Glu or L-Lys NCAs, to display functionalities found in native mucin proteins (see SI Appendix, Tables S2-S4, for copolymerization data) (30). Copolypeptide structures correlated well to monomer feed ratios, and the native α-glycosidic linkage was found to be stable to the acidic and basic deprotection conditions required to remove the tBu and TFA groups from Glu and Lys, respectively (according to 1 H NMR; SI Appendix, Tables S2-S4).…”

Section: Significancementioning

confidence: 99%

Chemically tunable mucin chimeras assembled on living cells

Kramer

Onoa

Bustamante

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

133

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Mucins are a family of secreted and transmembrane glycoproteins characterized by a massive domain of dense O-glycosylation on serine and threonine residues. Mucins are intimately involved in immunity and cancer, yet elucidation of the biological roles of their glycodomains has been complicated by their massive size, domain polymorphisms, and variable glycosylation patterns. Here we developed a synthetic route to a library of compositionally defined, high-molecular weight, dual end-functionalized mucin glycodomain constructs via N-carboxyanhydride polymerization. These glycopolypeptides are the first synthetic analogs to our knowledge to feature the native α-GalNAc linkage to serine with molecular weights similar to native mucins, solving a nearly 50-year synthetic challenge. Physical characterization of the mimics revealed insights into the structure and properties of mucins. The synthetic glycodomains were end-functionalized with an optical probe and a tetrazine moiety, which allowed site-specific bioorthogonal conjugation to an engineered membrane protein on live mammalian cells. This strategy in protein engineering will open avenues to explore the biological roles of cell surface mucins.

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Section: Significancementioning

confidence: 99%

Chemically tunable mucin chimeras assembled on living cells

Kramer

Onoa

Bustamante

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

133

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“…It has been used extensively as a reporter protein onto which cytoplasmic sorting sequences can be appended to demonstrate the trafficking function of these sequences (22)(23)(24)(25)(26). Tac normally enters cells via CIE (27,28).…”

Section: Resultsmentioning

confidence: 99%

“…First, Tac is targeted to the plasma membrane by default and has been extensively used to delineate cytoplasmic sorting signals (22,25,26,44). Tac itself is a model CIE protein whose internalization and trafficking kinetics mimic those of endogenous CIE cargo such as major histocompatibility complex class I (MHCI) (27).…”

Section: Discussionmentioning

confidence: 99%

Roles for Trafficking and O-Linked Glycosylation in the Turnover of Model Cell Surface Proteins

Karabasheva

Cole

Donaldson

2014

Journal of Biological Chemistry

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Background: Plasma membrane proteins can be degraded by a number of mechanisms. Results: Turnover rates are determined by endocytosis signals and trafficking to lysosomes, ubiquitination, and ectodomain cleavage. Conclusion: Membrane trafficking to lysosomes and proteolysis at the cell surface determine protein half-life. Significance: Learning how plasma membrane proteins are turned over is critical for understanding protein homeostasis.

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“…However, galectin-3 is not a general receptor for apical sorting in epithelial cells. Apical sorting of the soluble glycosylated growth hormone (gGH), the sialomucin endolyn, MUC1 or lipid-raft-associated sucrase isomaltase (SI) is not influenced by depletion of galectin-3 (Delacour et al, 2006;Kinlough et al, 2011;Mattila et al, 2012;Mo et al, 2012). Neither does apical transcytosis of the transferrin receptor (TfR) depend on galectin-3 (Perez Bay et al, 2014).…”

Section: Participation Of Galectin-3 In Apical Traffickingmentioning

confidence: 99%