Journal: Nat Commun / Year: 2017 Title: Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase. Authors: Sina Reckel / Charlotte Gehin / Delphine Tardivon / Sandrine Georgeon / Tim Kükenshöner / Frank Löhr / Akiko Koide / Lena Buchner / Alejandro Panjkovich / Aline Reynaud / Sara Pinho / ...Authors: Sina Reckel / Charlotte Gehin / Delphine Tardivon / Sandrine Georgeon / Tim Kükenshöner / Frank Löhr / Akiko Koide / Lena Buchner / Alejandro Panjkovich / Aline Reynaud / Sara Pinho / Barbara Gerig / Dmitri Svergun / Florence Pojer / Peter Güntert / Volker Dötsch / Shohei Koide / Anne-Claude Gavin / Oliver Hantschel / Abstract: The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To ...The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study the Dbl-homology (DH) and Pleckstrin-homology (PH) domains of Bcr-Abl p210, which constitute the only structural differences to p190. Here we report high-resolution structures of the DH and PH domains and characterize conformations of the DH-PH unit in solution. Our structural and functional analyses show no evidence that the DH domain acts as a guanine nucleotide exchange factor, whereas the PH domain binds to various phosphatidylinositol-phosphates. PH-domain mutants alter subcellular localization and result in decreased interactions with p210-selective interaction partners. Hence, the PH domain, but not the DH domain, plays an important role in the formation of the differential p210 and p190 Bcr-Abl signaling networks.
Instrument name: PETRA III P12 / City: Hamburg / 国: Germany / Type of source: X-ray synchrotronSynchrotron / Wavelength: 0.124 Å / Dist. spec. to detc.: 3 mm
Detector
Name: Pilatus 2M
Scan
Title: PH - Pleckstrin-homology domain of Bcr-Abl tyrosine kinase p210 Measurement date: Nov 10, 2016 / Storage temperature: 10 °C / Cell temperature: 10 °C / Exposure time: 0.045 sec. / Number of frames: 20 / Unit: 1/A /
Min
Max
Q
0.0021
0.379
Distance distribution function P(R)
Sofotware P(R): GNOM 5.0 / Number of points: 1500 /
Min
Max
Q
0.0071425
0.319587
P(R) point
1
1500
R
0
67
Result
Type of curve: merged Comments: The homology model is derived from PDB ID: 2z0q. The PDB entry for BCR-ABL p210 fusion protein PH domain is 5oc7 (has an internal deletion).
Experimental
Standard
Standard error
Porod
MW
23 kDa
16 kDa
3
23 kDa
Volume
-
-
-
38 nm3
P(R)
P(R) error
Guinier
Guinier error
Forward scattering, I0
2074
9
2071.9
9.84
Radius of gyration, Rg
2.07 nm
0.02
2.04 nm
0.03
Min
Max
Error
D
-
6.6
0.3
Guinier point
26
296
-
+
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