Sandbox Reserved 822: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 5: | Line 5: | ||
== '''Description''' == | == '''Description''' == | ||
1W1H is a 4 chain structure of the human pleckstrin homology (PH) domain of the 3-phosphoinositide-dependent protein kinase 1 (PDK1), which plays a various role in PI3K signaling pathways. | 1W1H is a 4 chain structure of the human pleckstrin homology (PH) domain of the [[3-phosphoinositide-dependent protein kinase 1]] (PDK1), which plays a various role in PI3K signaling pathways. | ||
PDK1 contains 556 amino acids and phosphorylates and activates at least 24 Proteins of the AGC (cAMP-dependent, cGMP-dependent, protein kinase C (PKC)) family of protein kinases. It therefore consists of a N-terminal Ser/Thr kinase catalytic domain (residues 71-359) and the C-terminal pleckstrin homology (PH) domain (residues 459-550). | PDK1 contains 556 amino acids and phosphorylates and activates at least 24 Proteins of the AGC (cAMP-dependent, cGMP-dependent, protein kinase C (PKC)) family of protein kinases. It therefore consists of a N-terminal Ser/Thr kinase catalytic domain (residues 71-359) and the C-terminal pleckstrin homology (PH) domain (residues 459-550). | ||
| Line 33: | Line 33: | ||
=== Binding site === | === Binding site === | ||
The <scene name='56/568020/Active_site/1'>binding site</scene> is formed by VL 1-3 which create a shallow, positively charged pocket at the open end of the β barrel. The structure was determined from a crystal grown in the presence of Ins(1,3,4,5)P<sub>4</sub>, which is the head group of PtdIns(3,4,5)P<sub>3</sub>. The phosphoinositide-binding site is lined by positively charged residues which contact the phosphates of Ins(1,3,4,5)P<sub>4</sub> by forming up to 11 hydrogen bonds. <scene name='56/568020/Arg472/1'>Arg472</scene> forms two hydrogen bonds to the phosphate in the D1 position (D1-phosphate). <scene name='56/568020/Argandlys/1'>Arg474 and Lys465</scene> contact the D3-phosphate with three hydrogen bonds in total (two for Arg474, one for Lys465). <scene name='56/568020/Lys495/1'>Lys495</scene> is also in close proximity (4.4 Å) of the D3-phosphate and is able to interact with it. <scene name='56/568020/Lys_tyr_and_arg/2'>Lys465, Tyr486 and Arg521</scene> form up to four hydrogen bonds to the D4-phosphate. The D5-phosphate is contacted by <scene name='56/568020/Lys467/1'>Lys467</scene> with one hydrogen bond. The D2- and D6-hydroxy groups show no direct interactions with the protein. | The <scene name='56/568020/Active_site/1'>binding site</scene> is formed by VL 1-3 which create a shallow, positively charged pocket at the open end of the β barrel. The structure was determined from a crystal grown in the presence of Ins(1,3,4,5)P<sub>4</sub>, which is the head group of PtdIns(3,4,5)P<sub>3</sub>. The phosphoinositide-binding site is lined by positively charged residues which contact the phosphates of Ins(1,3,4,5)P<sub>4</sub> by forming up to 11 hydrogen bonds. <scene name='56/568020/Arg472/1'>Arg472</scene> forms two hydrogen bonds to the phosphate in the D1 position (D1-phosphate). <scene name='56/568020/Argandlys/1'>Arg474 and Lys465</scene> contact the D3-phosphate with three hydrogen bonds in total (two for Arg474, one for Lys465). <scene name='56/568020/Lys495/1'>Lys495</scene> is also in close proximity (4.4 Å) of the D3-phosphate and is able to interact with it. <scene name='56/568020/Lys_tyr_and_arg/2'>Lys465, Tyr486 and Arg521</scene> form up to four hydrogen bonds to the D4-phosphate. The D5-phosphate is contacted by <scene name='56/568020/Lys467/1'>Lys467</scene> with one hydrogen bond. The D2- and D6-hydroxy groups show no direct interactions with the protein. | ||
== Physiological Relevance == | |||
=== Role in Signaling === | |||
Once activated by growth factors, various local responses, such as cell growth, cell survival and cell movement are regulated by the highly conserved PDK1 pathway. | |||
Therefore PDK1 binds to the lipid products of [[PI3K]], PtdIns(3,4,5)P<sub>3</sub> and PtdIns(3,4)P<sub>2</sub> (see 'Ligand Interaction'). Once localized to the plasma membrane PDK1 can phosphorylate PKB/Akt and thereby activate mTOR, which plays a major role in age mechanisms and Alzheimer’s disease. Other tumor supressors such as the phosphatidylinositol 3′-phosphatase PTEN act to down-regulate signaling from PI3K to PDK1 and PKB as well. | |||
Some other substrates of PDK1 are usually activated when the lipid-binding function of the protein is interrupted. Hence, not all PDK1 mediated reactions depend necessarily on the PH domain of PDK1. | |||
== References == | == References == | ||
<references/> | <references/> | ||
