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TF_Li_Manuscript_ChemRxiv_Dec15_2020.pdf (1.13 MB)

Sialylation Fine-Tunes Glycoprotein Structural Microheterogeneity Associated with Alzheimer’s Disease as Captured by Native Ion Mobility-Mass Spectrometry

submitted on 15.12.2020, 17:36 and posted on 16.12.2020, 13:07 by Gongyu Li, Ashley Phetsanthad, Min Ma, Qinying Yu, Ashita Nair, Zhen Zheng, Kellen DeLaney, Fengfei Ma, Seungpyo Hong, Lingjun Li
Protein sialylation has been closely linked to many diseases including Alzheimer’s disease (AD) and is broadly implicated in therapeutics in a terminal structure-sensitive manner. However, how sialylation structurally affects mature glycoproteins and how such effect is linked biochemically to AD progression largely remain ill-defined and are, likely beset with the lack of appropriate strategies capable of rapid and in situ manipulation of sialic acids on mature glycoproteins. Herein, we report the use of native ion mobility-mass spectrometry (IM-MS)-based structural probing methodology, enabling well-controlled, synergistic and in situ manipulation of mature glycoproteins and attached sialic acids. Cell viability experiments and IM-MS suggest that the dysregulating effects of transferrin sialylation on the iron-enhanced Aβ cytotoxicity acts through sialylation-dependent Aβ and iron co-importing pathway. Meanwhile, native gel electrophoresis and IM-MS reveal the sialylation-regulated transferrin dimerization tendency. Collectively, IM-MS is adapted to capture key sialylation intermediates involved in fine-tuning AD-associated glycoprotein structural micoheterogeneity. Our results may shed new lights on AD-modifying strategies based on sialylation-regulated glycoprotein functions and cytotoxicity.


Email Address of Submitting Author


University of Wisconsin-Madison


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

No Conflict of Interest.