SASDC26: DH-PH - Dbl-homology domain (DH) and Pleckstrin-homology (PH) of ...

Basic information

• Entry: Database: SASBDB / ID: SASDC26

Sample

DH-PH - Dbl-homology domain (DH) and Pleckstrin-homology (PH) of Bcr-Abl tyrosine kinase p210

• BCR-ABL p210 fusion protein (DH-PH) (protein), Homo sapiens

Function / homology

Function:

negative regulation of respiratory burst / negative regulation of cellular extravasation / negative regulation of macrophage migration / neutrophil degranulation / negative regulation of blood vessel remodeling / negative regulation of neutrophil degranulation / macrophage migration / intracellular protein transmembrane transport / renal system process / regulation of vascular permeability / regulation of Rho protein signal transduction / focal adhesion assembly / Signaling by cytosolic FGFR1 fusion mutants / definitive hemopoiesis / activation of GTPase activity / regulation of small GTPase mediated signal transduction / inner ear morphogenesis / small GTPase-mediated signal transduction / RHOB GTPase cycle / RHOC GTPase cycle / CDC42 GTPase cycle / neuromuscular process controlling balance / homeostasis of number of cells / RHOA GTPase cycle / negative regulation of reactive oxygen species metabolic process / RAC2 GTPase cycle / RAC3 GTPase cycle / phagocytosis / positive regulation of phagocytosis / keratinocyte differentiation / RAC1 GTPase cycle / Signaling by FGFR1 in disease / GTPase activator activity / guanyl-nucleotide exchange factor activity / brain development / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / negative regulation of inflammatory response / actin cytoskeleton organization / protein tyrosine kinase activity / cellular response to lipopolysaccharide / dendritic spine / postsynaptic density / non-specific serine/threonine protein kinase / regulation of cell cycle / protein phosphorylation / axon / protein serine kinase activity / protein serine/threonine kinase activity / glutamatergic synapse / signal transduction / protein-containing complex / extracellular exosome / ATP binding / membrane / plasma membrane / cytosol

Domain/homology:

Bcr-Abl oncoprotein oligomerisation / Bcr-Abl oncoprotein oligomerisation domain superfamily / Abr/Bcr / Bcr-Abl oncoprotein oligomerisation domain / PH domain / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Rho GTPase activation protein / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 domain profile. / C2 domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily

Component:

Breakpoint cluster region protein

• Biological species: Homo sapiens (human)
• Citation: 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 / 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 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.

Contact author

• Alejandro Panjkovich (EMBL-Hamburg, European Molecular Biology Laboratory (EMBL) - Hamburg outstation, Notkestraße 85, Geb. 25A, 22607 Hamburg, Deutschland, Germany)

Models

• Model #1390: ; Type: mix / Radius of dummy atoms: 1.90 A / Chi-square value: 0.993; Search similar-shape structures of this assembly by Omokage search (details)
• Model #1391: ; Type: mix / Radius of dummy atoms: 1.90 A / Chi-square value: 0.993; Search similar-shape structures of this assembly by Omokage search (details)
• Model #1392: ; Type: mix / Radius of dummy atoms: 1.90 A / Chi-square value: 0.993; Search similar-shape structures of this assembly by Omokage search (details)
• Model #1393: ; Type: mix / Radius of dummy atoms: 1.90 A / Chi-square value: 0.993; Search similar-shape structures of this assembly by Omokage search (details)

Sample

• Sample: Name: DH-PH - Dbl-homology domain (DH) and Pleckstrin-homology (PH) of Bcr-Abl tyrosine kinase p210; Specimen concentration: 1.80-14.40
• Buffer: Name: 25 mM Tris-HCl, 150 mM NaCl, 5% Glycerol, 1 mM DTT / pH: 7.5

Entity #738

Type: protein / Description: BCR-ABL p210 fusion protein (DH-PH) / Formula weight: 47.133 / Num. of mol.: 1 / Source: Homo sapiens / References: UniProt: P11274
Sequence:

GAMASELDLE KGLEMRKWVL SGILASEETY LSHLEALLLP MKPLKAAATT SQPVLTSQQI ETIFFKVPEL YEIHKEFYDG LFPRVQQWSH QQRVGDLFQK LASQLGVYRA FVDNYGVAME MAEKCCQANA QFAEISENLR ARSNKDAKDP TTKNSLETLL YKPVDRVTRS TLVLHDLLKH TPASHPDHPL LQDALRISQN FLSSINEEIT PRRQSMTVKK GEHRQLLKDS FMVELVEGAR KLRHVFLFTD LLLCTKLKKQ SGGKTQQYDC KWYIPLTDLS FQMVDELEAV PNIPLVPDEE LDALKIKISQ IKNDIQREKR ANKGSKATER LKKKLSEQES LLLLMSPSMA FRVHSRNGKS YTFLISSDYE RAEWRENIRE QQKKCFRSFS LTSVELQMLT NSCVKLQTVH

Experimental information

• Beam: Instrument name: PETRA III P12 / City: Hamburg / 国: Germany / Type of source: X-ray synchrotron / Wavelength: 0.124 Å / Dist. spec. to detc.: 3 mm
• Detector: Name: Pilatus 2M

Scan

Title: DH-PH - Dbl-homology domain (DH) and Pleckstrin-homology (PH) of Bcr-Abl p210
Measurement date: Oct 13, 2015 / Storage temperature: 20 °C / Cell temperature: 20 °C / Exposure time: 0.045 sec. / Number of frames: 20 / Unit: 1/A /

	Min	Max
Q	0.0025	0.4812

Distance distribution function P(R)

Sofotware P(R): GNOM 4.5a / Number of points: 464 /

	Min	Max
Q	0.006353	0.251
P(R) point	1	464
R	0	111.4

Result

Type of curve: merged

	Experimental	Standard	Standard error	Porod
MW	41 kDa	41 kDa	2	42 kDa
Volume	-	-	-	69 nm3

	P(R)	Guinier	Guinier error	P(R) error
Forward scattering, I0	10100	10070.7	18.2	-
Radius of gyration, Rg	2.16 nm	3.18 nm	0.03	0.02

	Min	Max	Error
D	-	11.1	0.3
Guinier point	16	143	-