Post-translational Modifications in the Human Proteome

Lichti, Cheryl F.; Wildburger, Norelle C.; Emmett, Mark R.; Mostovenko, Ekaterina; Shavkunov, Alexander S.; Strain, Shinji; Nilsson, Carol L.

doi:10.1007/978-94-017-9202-8_6

Cited by 2 publications

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References 223 publications

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“…Modifications change proteins’ physicochemical and biochemical properties to produce a wide array of biomolecules that increase the range of functional outcomes in a biological system ( Lichti et al, 2014 ; Aebersold et al, 2018 ; Smith and Kelleher, 2018 ). These proteoforms are either stable or dynamic and can locally or globally change in response to developmental signals, normal stimuli, aging, or disease—and in many cases the modifications drive these processes.…”

Section: Proteoformsmentioning

confidence: 99%

“…The addition of a phosphoryl group (PO 3 – ) to biomolecules is the one of the most well-studied PTMs. Phosphorylation can occur on serine (S), threonine (T), and tyrosine (Y) side chains and is traditionally viewed as a molecular on/off switch, but it can also have consequences for protein-protein binding characteristics and/or subcellular localization ( Lichti et al, 2014 ). aSyn has a number of available phosphorylation sites (18 in total; 4 S, 4 T, and 10 Y), but only a few have been described and investigated.…”

Section: Asyn Proteoforms and Their Impact On Lysosomal Functionmentioning

confidence: 99%

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Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms

Wildburger

Hartke

Schidlitzki

et al. 2020

Front. Cell Dev. Biol.

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Cumulative evidence collected in recent decades suggests that lysosomal dysfunction contributes to neurodegenerative diseases, especially if amyloid proteins are involved. Among these, alpha-synuclein (aSyn) that progressively accumulates and aggregates in Lewy bodies is undisputedly a main culprit in Parkinson disease (PD) pathogenesis. Lysosomal dysfunction is evident in brains of PD patients, and mutations in lysosomal enzymes are a major risk factor of PD. At first glance, the role of protein-degrading lysosomes in a disease with pathological protein accumulation seems obvious and should guide the development of straightforward and rational therapeutic targets. However, our review demonstrates that the story is more complicated for aSyn. The protein can possess diverse posttranslational modifications, aggregate formations, and truncations, all of which contribute to a growing known set of proteoforms. These interfere directly or indirectly with lysosome function, reducing their own degradation, and thereby accelerating the protein aggregation and disease process. Conversely, unbalanced lysosomal enzymatic processes can produce truncated aSyn proteoforms that may be more toxic and prone to aggregation. This highlights the possibility of enhancing lysosomal function as a treatment for PD, if it can be confirmed that this approach effectively reduces harmful aSyn proteoforms and does not produce novel, toxic proteoforms.

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Section: Proteoformsmentioning

confidence: 99%

Section: Asyn Proteoforms and Their Impact On Lysosomal Functionmentioning

confidence: 99%