Retinoblastoma protein
From Proteopedia
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| 1o9k, resolution 2.60Å () | |||||||||
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| Related: | 1pjm, 1n4m, 1h24, 1ad6, 1h25, 1gh6, 1gux, 2aze | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
Retinoblastoma Protein (pRB)
The is a tumor suppressor protein that prevents excessive cell growth. If not mutated, it is present in our cells and blocks the growth of dysfunctional cells between the G1 and S phase of the cell cycle before they can undergo DNA replication. pRB regulates the function of cyclin and cyclin dependent kinase (CDK) complexes which are needed for the cell to proceed cell growth. Retinoblastoma protein is dependent on the transcription factor E2F, which is bound to pRB's active site when it is dephosphorylated. In viral cells, and in tumorous cells pRB is dysfunctional or completely lost.
pRb/EF binding in the cell cycle
A cell must go through the cell cycle in order to grow, and replicate. Before the cell can replicate it has to pass through the many phases of the cell cycle (have a picture of the cell cycle). There’s the Go phase also known as the resting phase in which the cell can remain dormant forever. Then G1 phase in which cell growth takes place. Next is R-phase restriction point which determines if the cell is ready to move on to the S phase, which is when the cell’s DNA is replicated. It moves on to the G2 phase and finally the M-phase where it divides. The phases where pRB function is necessary are during the Go phase, and during the restriction point that determines the transition from the G1 phase to the S phase. During these phases, the cell is deciding whether it will move on to the S-phase where it will replicate its DNA. If the cell is not growing adequately, for example if its DNA is damaged, then the retinoblastoma protein will dephosphorylate and bind to the E2F transcription factor, this causes the inhibition of E2F and of cyclin CDK complexes. When pRB is phosphorylated, it no longer inhibits cell growth and the cell can continue developing.
Specific Binding sites of pRb/E2F complex
When pRB and E2F form a complex, pRB is activated, and therefore inhibits cell growth. This complex is held together by many weak interactions, such as hydrophobic and hydrogen bond interactions. The retinoblastoma protein’s active site is composed of two domains. Domians A and B (zoom into the A and B domains), which form the pRB pocket domain that E2F can bind to, the C-terminal residues on pRb are also necessary for E2F to bind tightly. Specifically, E2F binds to the α4, α5, α6, α8, and α9 of the A domain, and only bind to the α11 of the B domain (put in figure). This structure was obtained through a diffraction image from a diffractometer (reference). They also found that of the entire E2Fcomplex only the two end regions make contact with pRB while the middle region, which contains residues 416-420, does not interact with pRB.
(highlight the E2F peptide)There are 18 residues of the E2F protein that are involved in the pRb/E2F complex, residues 409-426. Within this E2Fregion, there are 5 essential amino acids that if altered, would cause the complex to fall apart. These amino acids are the following: Tyr(411) binds to pRB via a hydrophobic pocket created by phenolic ring, and a hydrogen bond created by the hydroxyl group on the phenol ring(zoom into that area). Leu(424) and Phe(425) both form many hydrophobic interactions. Glu(419) hydrogen bonds to Thr(645) of pRB, and Aps(423) forms a salt bridge with Arg(467) on pRB (reference). Any point mutations of any of these amino acids will block binding of pRb, leading to deactivation of pRb’s cell inhibiting function, and will allow E2F to promote the cell cycle to move on to the S-phase.
Inhibition/ Activation of pRB
Retinoblastoma, Tumors, and Cancer
Proteopedia Page Contributors and Editors (what is this?)
Yvonne Alva, Michal Harel, Joel L. Sussman, Alexander Berchansky
