Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221]
Paradoxically, aggregation of specific proteins is characteristic of many human diseases and aging, yet aggregates have been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology and dynamics of a helical mutant in a membrane environment transformed from the 125-re...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
F1000 Research Ltd
2013-10-01
|
| Series: | F1000Research |
| Subjects: | |
| Online Access: | http://f1000research.com/articles/2-221/v1 |
| _version_ | 1818939124648771584 |
|---|---|
| author | Haina Qin Liangzhong Lim Yuanyuan Wei Garvita Gupta Jianxing Song |
| author_facet | Haina Qin Liangzhong Lim Yuanyuan Wei Garvita Gupta Jianxing Song |
| author_sort | Haina Qin |
| collection | DOAJ |
| description | Paradoxically, aggregation of specific proteins is characteristic of many human diseases and aging, yet aggregates have been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology and dynamics of a helical mutant in a membrane environment transformed from the 125-residue cytosolic all-β MSP by the ALS-causing P56S mutation. Unexpectedly, despite its low hydrophobicity, the P56S major sperm protein (MSP) domain becomes largely embedded in the membrane environment with high backbone rigidity. Furthermore it is composed of five helices with amphiphilicity comparable to those of the partly-soluble membrane toxin mellitin and α-synuclein causing Parkinson's disease. Consequently, the mechanism underlying this chameleon transformation becomes clear: by disrupting the specific tertiary interaction network stabilizing the native all-β MSP fold to release previously-locked amphiphilic segments, the P56S mutation acts to convert the classic MSP fold into a membrane-active protein that is fundamentally indistinguishable from mellitin and α-synuclein which are disordered in aqueous solution but spontaneously partition into membrane interfaces driven by hydrogen-bond energetics gained from forming α-helix in the membrane environments. As segments with high amphiphilicity exist in all proteins, our study successfully resolves the paradox by deciphering that the proteins with a higher tendency to aggregate have a stronger potential to partition into membranes through the same mechanism as α-synuclein to initially attack membranes to trigger pathogenesis without needing aggregates. This might represent the common first step for various kinds of aggregated proteins to trigger familiar, sporadic and aging diseases. Therefore the homeostasis of aggregated proteins in vivo is the central factor responsible for a variety of human diseases including aging. The number and degree of the membrane attacks by aggregated proteins may act as an endogenous clock to count down the aging process. Consequently, a key approach to fight against them is to develop strategies and agents to maintain or even enhance the functions of the degradation machineries. |
| first_indexed | 2024-12-20T06:18:46Z |
| format | Article |
| id | doaj.art-bc195c8622604b06a7c1137f80d9e97b |
| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-12-20T06:18:46Z |
| publishDate | 2013-10-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj.art-bc195c8622604b06a7c1137f80d9e97b2022-12-21T19:50:29ZengF1000 Research LtdF1000Research2046-14022013-10-01210.12688/f1000research.2-221.v12665Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221]Haina Qin0Liangzhong Lim1Yuanyuan Wei2Garvita Gupta3Jianxing Song4Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 119260, SingaporeDepartment of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 119260, SingaporeNUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 119260, SingaporeDepartment of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 119260, SingaporeNUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, 119260, SingaporeParadoxically, aggregation of specific proteins is characteristic of many human diseases and aging, yet aggregates have been found to be unnecessary for initiating pathogenesis. Here we determined the NMR topology and dynamics of a helical mutant in a membrane environment transformed from the 125-residue cytosolic all-β MSP by the ALS-causing P56S mutation. Unexpectedly, despite its low hydrophobicity, the P56S major sperm protein (MSP) domain becomes largely embedded in the membrane environment with high backbone rigidity. Furthermore it is composed of five helices with amphiphilicity comparable to those of the partly-soluble membrane toxin mellitin and α-synuclein causing Parkinson's disease. Consequently, the mechanism underlying this chameleon transformation becomes clear: by disrupting the specific tertiary interaction network stabilizing the native all-β MSP fold to release previously-locked amphiphilic segments, the P56S mutation acts to convert the classic MSP fold into a membrane-active protein that is fundamentally indistinguishable from mellitin and α-synuclein which are disordered in aqueous solution but spontaneously partition into membrane interfaces driven by hydrogen-bond energetics gained from forming α-helix in the membrane environments. As segments with high amphiphilicity exist in all proteins, our study successfully resolves the paradox by deciphering that the proteins with a higher tendency to aggregate have a stronger potential to partition into membranes through the same mechanism as α-synuclein to initially attack membranes to trigger pathogenesis without needing aggregates. This might represent the common first step for various kinds of aggregated proteins to trigger familiar, sporadic and aging diseases. Therefore the homeostasis of aggregated proteins in vivo is the central factor responsible for a variety of human diseases including aging. The number and degree of the membrane attacks by aggregated proteins may act as an endogenous clock to count down the aging process. Consequently, a key approach to fight against them is to develop strategies and agents to maintain or even enhance the functions of the degradation machineries.http://f1000research.com/articles/2-221/v1Cognitive Neurology & DementiaMembrane Proteins & Energy TransductionMembranes & SortingNeuronal & Glial Cell BiologyProtein Folding |
| spellingShingle | Haina Qin Liangzhong Lim Yuanyuan Wei Garvita Gupta Jianxing Song Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221] F1000Research Cognitive Neurology & Dementia Membrane Proteins & Energy Transduction Membranes & Sorting Neuronal & Glial Cell Biology Protein Folding |
| title | Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221] |
| title_full | Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221] |
| title_fullStr | Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221] |
| title_full_unstemmed | Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221] |
| title_short | Resolving the paradox for protein aggregation diseases: a common mechanism for aggregated proteins to initially attack membranes without needing aggregates [v1; ref status: indexed, http://f1000r.es/221] |
| title_sort | resolving the paradox for protein aggregation diseases a common mechanism for aggregated proteins to initially attack membranes without needing aggregates v1 ref status indexed http f1000r es 221 |
| topic | Cognitive Neurology & Dementia Membrane Proteins & Energy Transduction Membranes & Sorting Neuronal & Glial Cell Biology Protein Folding |
| url | http://f1000research.com/articles/2-221/v1 |
| work_keys_str_mv | AT hainaqin resolvingtheparadoxforproteinaggregationdiseasesacommonmechanismforaggregatedproteinstoinitiallyattackmembraneswithoutneedingaggregatesv1refstatusindexedhttpf1000res221 AT liangzhonglim resolvingtheparadoxforproteinaggregationdiseasesacommonmechanismforaggregatedproteinstoinitiallyattackmembraneswithoutneedingaggregatesv1refstatusindexedhttpf1000res221 AT yuanyuanwei resolvingtheparadoxforproteinaggregationdiseasesacommonmechanismforaggregatedproteinstoinitiallyattackmembraneswithoutneedingaggregatesv1refstatusindexedhttpf1000res221 AT garvitagupta resolvingtheparadoxforproteinaggregationdiseasesacommonmechanismforaggregatedproteinstoinitiallyattackmembraneswithoutneedingaggregatesv1refstatusindexedhttpf1000res221 AT jianxingsong resolvingtheparadoxforproteinaggregationdiseasesacommonmechanismforaggregatedproteinstoinitiallyattackmembraneswithoutneedingaggregatesv1refstatusindexedhttpf1000res221 |