Insights into the molecular mechanism of protein native-like aggregation upon glycation

Oliveira, Luís M. A.; Gomes, Ricardo A.; Yang, Dennis T.; Dennison, Sarah Rachel; Família, Carlos; Lages, Ana; Coelho, Ana Varela; Murphy, Regina M.; Phoenix, David A.; Quintas, Alexandre

doi:10.1016/j.bbapap.2012.12.001

Cited by 50 publications

(34 citation statements)

References 60 publications

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“…Our study demonstrates that glycation of HEWL promotes aggregation but no fibrillar species was observed. Recent studies have shown that methylglyoxal (glycating agent) favors formation of native like aggregates of insulin [41] and cytochrome c [42]. This study will be beneficial in terms of understanding the effects of glycation on the structural aspects of proteins and its consequences in protein aggregation.…”

Section: Introductionmentioning

confidence: 99%

Prolonged Glycation of Hen Egg White Lysozyme Generates Non Amyloidal Structures

et al. 2013

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Glycation causes severe damage to protein structure that could lead to amyloid formation in special cases. Here in this report, we have shown for the first time that hen egg white lysozyme (HEWL) does not undergo amyloid formation even after prolonged glycation in the presence of D-glucose, D-fructose and D-ribose. Cross-linked oligomers were formed in all the cases and ribose was found to be the most potent among the three sugars. Ribose mediated oligomers, however, exhibit Thioflavin T binding properties although microscopic images clearly show amorphous and globular morphology of the aggregates. Our study demonstrates that the structural damage of hen egg white lysozyme due to glycation generates unstructured aggregates.

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Section: Introductionmentioning

confidence: 99%

Prolonged Glycation of Hen Egg White Lysozyme Generates Non Amyloidal Structures

et al. 2013

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“…The same study observed that the formation of glycated cytochrome c unfolded species is an off-pathway of the native-like aggregation route. The authors suggest that glycation of amyloidogenic proteins may lead to a shift from an amyloidogenic pathway to a native-like aggregation through a process that is thermodynamically and kinetically favoured 32 . Taking together the observations previously presented, what emerges is a preliminary picture of the driving forces that make an amyloidogenic protein follow a route of native-like aggregation.…”

Section: What Drives An Amyloidogenic Protein Into a Native-like Aggrmentioning

confidence: 99%

“…Unlike amyloidogenesis, native-like aggregation pathways do not present an unfolding specie to trigger oligomerization 33,34 . In fact, native-like aggregation seems to proceed by stacking of near-native protein intermediates towards oligomeric species of inite size 32,33 ( Figure 6). In humans, native-like aggregation has been described in a very small group of proteins.…”

Section: Intrinsically Unfolded Protein As Amyloid Precursorsmentioning

confidence: 99%

“…α-synuclein amyloid ibril formation seems to occur in the form of partially folded intermediate, pre-molten globule-like structure, the irst step for ibrillization 31 ( Figure 5). 13,32,33 . Unlike amyloidogenesis, native-like aggregation pathways do not present an unfolding specie to trigger oligomerization 33,34 .…”

Section: Intrinsically Unfolded Protein As Amyloid Precursorsmentioning

confidence: 99%

“…This means there is a zero-order kinetics step before the aggregation into amyloid takes place in such a way that at very high concentration of protein, native-like aggregation, a pure irst-order step, is favoured 33 . Recently, a model for native-like aggregation of methylglyoxal-glycated proteins has been proposed 32 . Native-like aggregation occurs due to localized protein structural changes leading to a decrease on the conformational stability of the modi ied protein.…”

Section: What Drives An Amyloidogenic Protein Into a Native-like Aggrmentioning

confidence: 99%

See 2 more Smart Citations

What drives an amyloid protein precursor from an amyloidogenic to a native-like aggregation pathway?

Quintas¹

2013

OA Biochemistry

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Glycation of Wild‐Type Apomyoglobin Induces Formation of Highly Cytotoxic Oligomeric Species

Iannuzzi

Carafa

Altucci

et al. 2015

Journal Cellular Physiology

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Protein glycation is a non-enzymatic, irreversible modification of protein amino groups by reactive carbonyl species leading to the formation of advanced glycation end products (AGEs). Several proteins implicated in neurodegenerative diseases have been found to be glycated in vivo and the extent of glycation is related to the pathologies of the patients. Although it is now accepted that there is a direct correlation between AGEs formation and the development of neurodegenerative diseases related to protein misfolding and amyloid aggregation, several questions still remain unanswered: whether glycation is the triggering event or just an additional factor acting on the aggregation pathway. We have recently shown that glycation of the amyloidogenic W7FW14F apomyoglobin mutant significantly accelerates the amyloid fibrils formation providing evidence that glycation actively participates to the process. In the present study, to test if glycation can be considered also a triggering factor in amyloidosis, we evaluated the ability of different glycation agents to induce amyloid aggregation in the soluble wild-type apomyoglobin. Our results show that glycation covalently modifies apomyoglobin and induces conformational changes that lead to the formation of oligomeric species that are not implicated in amyloid aggregation. Thus, AGEs formation does not trigger amyloid aggregation in the wild-type apomyoglobin but only induce the formation of soluble oligomeric species able to affect cell viability. The molecular bases of cell toxicity induced by AGEs formed upon glycation of wild-type apomyoglobin have been also investigated.

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Insights into the molecular mechanism of protein native-like aggregation upon glycation

Cited by 50 publications

References 60 publications

Prolonged Glycation of Hen Egg White Lysozyme Generates Non Amyloidal Structures

Prolonged Glycation of Hen Egg White Lysozyme Generates Non Amyloidal Structures

What drives an amyloid protein precursor from an amyloidogenic to a native-like aggregation pathway?

Glycation of Wild‐Type Apomyoglobin Induces Formation of Highly Cytotoxic Oligomeric Species

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