TY - JOUR
T1 - Cross-seeding and conformational selection between three- and four-repeat human Tau proteins
AU - Yu, Xiang
AU - Luo, Yin
AU - Dinkel, Paul
AU - Zheng, Jie
AU - Wei, Guanghong
AU - Margittai, Martin
AU - Nussinov, Ruth
AU - Ma, Buyong
PY - 2012/4/27
Y1 - 2012/4/27
N2 - In Alzheimer's disease and frontotemporal dementias, the microtubule-associated protein Tau forms intracellular paired helical filaments. The filaments can form not only by the full-length human Tau protein, but also by the three repeated (K19) or four repeated (K18) Tau segments. However, of interest, experimentally, K19 can seed K18, but not vice versa. To obtain insight into the cross-seeding between K18 and K19 aggregates, here, K18 and K19 octamers with repeat 3 (R3) in U-shaped, L-shaped, and long straight line-shaped (SL-shape) conformations are assembled into different structures. The simulation results show that K18-8/K19-8 (K18 and K19 assemblies number 8) with R3 in an L shape and K18-9/K19-9 with R3 in an SL shape are highly populated and present the highest structural similarity among all simulated K18 and K19 octamers, suggesting that similar folding of K18/K19 may serve as structural core for the K18-K19 co-assembled heterogeneous filament. We demonstrate that formation of stable R2 and R3 conformations is the critical step for K18 aggregation, and R3 is critical for K19 fibrillization. The different core units in K18 and K19 may create a cross-seeding barrier for the K18 seed to trigger K19 fibril growth because R2 is not available for K19. Our study provides insights into cross-seeding involving heterogeneous structures. The polymorphic nature of protein aggregation could be magnified in the cross-seeding process. If the seeding conformations lead to too much divergence in the energy landscape, it could impede fibril formation. Such an effect could also contribute to the asymmetric barrier between K18 and K19.
AB - In Alzheimer's disease and frontotemporal dementias, the microtubule-associated protein Tau forms intracellular paired helical filaments. The filaments can form not only by the full-length human Tau protein, but also by the three repeated (K19) or four repeated (K18) Tau segments. However, of interest, experimentally, K19 can seed K18, but not vice versa. To obtain insight into the cross-seeding between K18 and K19 aggregates, here, K18 and K19 octamers with repeat 3 (R3) in U-shaped, L-shaped, and long straight line-shaped (SL-shape) conformations are assembled into different structures. The simulation results show that K18-8/K19-8 (K18 and K19 assemblies number 8) with R3 in an L shape and K18-9/K19-9 with R3 in an SL shape are highly populated and present the highest structural similarity among all simulated K18 and K19 octamers, suggesting that similar folding of K18/K19 may serve as structural core for the K18-K19 co-assembled heterogeneous filament. We demonstrate that formation of stable R2 and R3 conformations is the critical step for K18 aggregation, and R3 is critical for K19 fibrillization. The different core units in K18 and K19 may create a cross-seeding barrier for the K18 seed to trigger K19 fibril growth because R2 is not available for K19. Our study provides insights into cross-seeding involving heterogeneous structures. The polymorphic nature of protein aggregation could be magnified in the cross-seeding process. If the seeding conformations lead to too much divergence in the energy landscape, it could impede fibril formation. Such an effect could also contribute to the asymmetric barrier between K18 and K19.
UR - http://www.scopus.com/inward/record.url?scp=84860380323&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.340794
DO - 10.1074/jbc.M112.340794
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AN - SCOPUS:84860380323
SN - 0021-9258
VL - 287
SP - 14950
EP - 14959
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 18
ER -