Avidity within the N-terminal anchor drives α-synuclein membrane interaction and insertion
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Avidity within the N-terminal anchor drives α-synuclein membrane interaction and insertion. / Cholak, Ersoy; Bugge, Katrine; Khondker, Adree; Gauger, Kimmie; Pedraz-Cuesta, Elena; Pedersen, Morten Enghave; Bucciarelli, Saskia; Vestergaard, Bente; Pedersen, Stine F.; Rheinstädter, Maikel C.; Langkilde, Annette Eva; Kragelund, Birthe B.
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 34, No. 6, 2020, p. 7462-7482.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Avidity within the N-terminal anchor drives α-synuclein membrane interaction and insertion
AU - Cholak, Ersoy
AU - Bugge, Katrine
AU - Khondker, Adree
AU - Gauger, Kimmie
AU - Pedraz-Cuesta, Elena
AU - Pedersen, Morten Enghave
AU - Bucciarelli, Saskia
AU - Vestergaard, Bente
AU - Pedersen, Stine F.
AU - Rheinstädter, Maikel C.
AU - Langkilde, Annette Eva
AU - Kragelund, Birthe B.
N1 - © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2020
Y1 - 2020
N2 - In the brain, α-synuclein (aSN) partitions between free unbound cytosolic and membrane bound forms modulating both its physiological and pathological role and complicating its study due to structural heterogeneity. Here, we use an interdisciplinary, synergistic approach to characterize the properties of aSN:lipid mixtures, isolated aSN:lipid co-structures, and aSN in mammalian cells. Enabled by the isolation of the membrane-bound state, we show that within the previously described N-terminal membrane anchor, membrane interaction relies both on an N-terminal tail (NTT) head group layer insertion of 14 residues and a folded-upon-binding helix at the membrane surface. Both binding events must be present; if, for example, the NTT insertion is lost, the membrane affinity of aSN is severely compromised and formation of aSN:lipid co-structures hampered. In mammalian cells, compromised cooperativity results in lowered membrane association. Thus, avidity within the N-terminal anchor couples N-terminal insertion and helical surface binding, which is crucial for aSN membrane interaction and cellular localization, and may affect membrane fusion.
AB - In the brain, α-synuclein (aSN) partitions between free unbound cytosolic and membrane bound forms modulating both its physiological and pathological role and complicating its study due to structural heterogeneity. Here, we use an interdisciplinary, synergistic approach to characterize the properties of aSN:lipid mixtures, isolated aSN:lipid co-structures, and aSN in mammalian cells. Enabled by the isolation of the membrane-bound state, we show that within the previously described N-terminal membrane anchor, membrane interaction relies both on an N-terminal tail (NTT) head group layer insertion of 14 residues and a folded-upon-binding helix at the membrane surface. Both binding events must be present; if, for example, the NTT insertion is lost, the membrane affinity of aSN is severely compromised and formation of aSN:lipid co-structures hampered. In mammalian cells, compromised cooperativity results in lowered membrane association. Thus, avidity within the N-terminal anchor couples N-terminal insertion and helical surface binding, which is crucial for aSN membrane interaction and cellular localization, and may affect membrane fusion.
U2 - 10.1096/fj.202000107R
DO - 10.1096/fj.202000107R
M3 - Journal article
C2 - 32277854
VL - 34
SP - 7462
EP - 7482
JO - F A S E B Journal
JF - F A S E B Journal
SN - 0892-6638
IS - 6
ER -
ID: 239561037