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PI 3-kinase Class III Structure

3D structure of human PI3K class III.

DOI:10.2210/pdb3ihy/pdb

 

This diagram shows crystal structure of human PI3K class III transferase obtained by X-ray diffraction with resolution of 2.80 Angstrom. The structure generated contains equal chains: A, B, C, D and E which is likely due to conditions in which crystals were created this only one chain is likely to be representative of the protein structure.  Domains are colour-coded. The structure shows only residues 282-879 obtained from the RSCB PDB website (PDB ID: 3IHY) [1] [2].

Predicted 3D strucuture of human PI3K class III

 

This diagram represents 3D structure predicted by the Phyre2 (Protein Homology/analogY Recognition Engine V 2.0) server from the FASTA sequence (accession number NP_002638). Domains are colour coded. The structure shows most of the protein sequence: residues 44- 876 thus all the domains were modelled. Despite model confidence being 100.0% the fact that the structure generated is a prediction from aminoacid sequence the actual protein may differ to the structure generated [3].

Functions of Domains

 

The Details of the Domains Observed Above:

Red- PI3K C2 domain

 

An N-terminal two four-stranded beta-pleated sheet structure forming beta-sandwich usually of about 130 aminoacid residues that binds Ca2+ ions and negatively charged phospholopid heads and is, therefore, frequently associated with membrane binding which is mediated by calcium ions. Proteins that contain C2 domain are either proteins involved in signal transduction( e.g. PI3K class III) or in membrane traffic (e.g. RIM). C2 domains can be both calcium dependent or calcium independent, PI3K is capable of both [4]. Calcium binding is conserved to top loops aspartate residues however other aminoacids are also involved in verious C2 domains. Binding calcium, however, does not induce a conformational change and it is proposed that the effect is induced by electrostatic changes allowing binding. The core part (the beta-sandwich) of the C2 domain is more conserved compared to loops which are diverse among C2 domains [5]. 

 

Violet- PI3K accessory (PI3Ka) domain

 

A protein domain conserved among PI3 and PI4-kinases. The structure of the domain consists of unparallel alpha helices with HEAT motifs (for protein-protein interactions) [4]. Its function of this domain is still unknown but it may play a role in substrate presentation [6]. 

 

Cyan- PI3K catalytic (PI3 PI4) domain

 

A C-terminal domain that contains most sites responsible for the function of the PI3K class III kinase. The sites are shown in the three diagrams below. This domain is highly conserved in various organisms [7].

 

  • Green (left image)- ATP binding site. This region is the most conserved part of the PI3K class III kinase. Site of ATP binding and phosphate transfer. 

  • Black (middle image)- catalytic loop. Movements of this loop maintains conformation required for chemical reactions [7] [8].

  • Indigo (right image)- activation loop. Eight aminoacid residues long onthe surface of the protein. This loop ensures substrate specificity, as shorter loop in PI3K class III kinases may prevent  4-phosphate from occupying the site but allowes binding of 5-phosphate of PtdIns [4].

References:

 

1.     Siponen, M.I., Tresaugues, L., Arrowsmith, C.H., Berglund, H., Bountra, C., Collins, R., Edwards, A.M., Flodin, S., Flores, A., Graslund, S., Hammarstrom, M., Johansson, A., Johansson, I., Karlberg, T., Kotenyova, T., Kotzsch, A., Kragh Nielsen, T., Moche, M., Nyman, T., Persson, C., Roos A.K., Sagemark, J., Schueler, H., Schutz, P., Thorsell, A.G., Van Den Berg, S., Weigelt, J., Welin, M., Wisniewska, M. & Nordlund, P. 2009. Human PIK3C3 crystal structure. TO BE PUBLISHED, null-null.

 

2.      Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. & Bourne, P.E. 2000. The protein data bank. Nucleic Acids Research, 28, 235-242.

 

3.      Kelley, L.A. & Sternberg, M.J. 2009. Protein structure prediction on the web:A case study using the Phyre server. Nature Protocols, 4, 363-371.

 

4.      Walker, E.H., Perisic, O., Ried, C., Stephens, L. & Williams, R.L. 1999. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature, 402, 313-320.

 

5.      Rizo, J. & Sudhof, T. C. 1998. C2-domains, structure and function of a universal Ca2+-binding domain. J Biol Chem, 273, 15879-82.

 

6.      Flanagan, C.A., Schnieders, E.A., Emerick, A.W., Kunisawa, R., Admon, A. & Thorner J. 1993. Phosphatidylinositol 4-kinase: gene structure and requirement for yeast cell viability. Science (New York, N.Y.), 262, 1444-1448.

 

7.      Stout, T. J., Foster, P. G. & Matthews, D. J. 2004. High-throughput structural biology in drug discovery: protein kinases. Current pharmaceutical design, 10, 1069-1082.

 

8.      Kurkcuoglu, Z., Bakan, A., Kocaman, D., Bahar, I. & Doruker P. 2012. Coupling between Catalytic Loop Motions and Enzyme Global Dynamics. PLoS Comput Biol, 8, e1002705.

 

N lobe

C lobe

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