User:Madison Unger/Sandbox 1

From Proteopedia

(Difference between revisions)

Revision as of 00:29, 24 March 2021

This is a default text for your page Madison Unger/Sandbox 1. Click above on edit this page to modify. Be careful with the < and > signs.

You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

1 Introduction
2 Structure
3 Proposed Mechanism
4 Disease
5 Relevance
6 Structural highlights

Introduction

We used an article on ACAT. ^[3] We also used an article on SOAT. ^[4]

Figure 1.Tetrameric dimer of dimer for ACAT

Acyl-coenzyme A: cholesterol acyltransferase (ACAT), also known as Human Sterol O-acyltransferase (hSOAT) is an enzyme that catalyzes the reaction between long chain fatty acyl CoA and intracellular cholesterol to form the more hydrophobic cholesteryl ester for cholesterol storage. Cholesteryl ester is the primary form of how cholesterol is stored in multiple types of cells and transported through the circulatory system. ACAT is an endoplasmic reticulum membrane protein, and ACAT is a part of the MBOAT (membrane-bound O-acyltransferase) family, which also includes acyl-coenzyme A: diacylglycerol acyltransferase (DGAT) and ghrelin O-acyltransferase (GOAT).

There have been two ACAT isoforms discovered in mammals, ACAT1 and ACAT2, and they are predominantly located in different parts of the body. ACAT1 is mainly found in the liver, kidneys, adrenal glands and macrophages, whereas ACAT2 is found only in the intestines and liver.

Structure

Overall Structure

ACAT is a tetramer composed of a dimer of a dimer, but is able to perform its function solely as a . There are in each domain which create a tunnel for the active site. There are also three helices found on the intracellular side (IH1, IH2, and IH3) and one helix on the extracellular side (EH1). The active site contains three tunnels – the transmembrane tunnel for cholesterol entrance, the cytosolic tunnel for acyl-CoA entrance, and the lumen tunnel for cholesterol ester exit. ACAT also has an amino-terminal cytosolic domain (NTD) that is important for tetramerization of this protein.

Important Residues

An important residue in the ACAT active site is His460, a Histidine, which is located in the middle of the tunnels. It is thought that His460 is located on TM7 (Qian et al.). When converting to a cholesteryl ester, the acts as a catalytic base that deprotonates the cholesterol. An asparagine Asn421 is another important residue in the reaction that is able to form a hydrogen bond with acyl-CoA for stabilization.

Important Interactions

Between the two protomers in each dimer, van der waals interactions occur between TM1 of one protomer and the lumenal TM6 and the cytosolic TM9 of the other protomer. The two dimers make limited contact within the membrane through an interface that is thought to be located between TM2, TM5, TM6 and IH2.

Proposed Mechanism

Error creating thumbnail:
libgomp: Thread creation failed: Resource temporarily unavailable

Figure 2: Proposed mechanism for ACAT

Active Site

Binding Pocket

Tunnels

Disease

Other Protopedia Page

Relevance

Structural highlights

This is a sample scene created with SAT to ">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.^[5]

References

↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
↑ Qian H, Zhao X, Yan R, Yao X, Gao S, Sun X, Du X, Yang H, Wong CCL, Yan N. Structural basis for catalysis and substrate specificity of human ACAT1. Nature. 2020 May;581(7808):333-338. doi: 10.1038/s41586-020-2290-0. Epub 2020 May, 13. PMID:32433614 doi:http://dx.doi.org/10.1038/s41586-020-2290-0
↑ Guan C, Niu Y, Chen SC, Kang Y, Wu JX, Nishi K, Chang CCY, Chang TY, Luo T, Chen L. Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor. Nat Commun. 2020 May 18;11(1):2478. doi: 10.1038/s41467-020-16288-4. PMID:32424158 doi:http://dx.doi.org/10.1038/s41467-020-16288-4
↑ Ransey E, Paredes E, Dey SK, Das SR, Heroux A, Macbeth MR. Crystal structure of the Entamoeba histolytica RNA lariat debranching enzyme EhDbr1 reveals a catalytic Zn(2+) /Mn(2+) heterobinucleation. FEBS Lett. 2017 Jul;591(13):2003-2010. doi: 10.1002/1873-3468.12677. Epub 2017, Jun 14. PMID:28504306 doi:http://dx.doi.org/10.1002/1873-3468.12677

Student Contributors

Leah Goehring
Gabby Smith
Anna Campbell

Proteopedia Page Contributors and Editors (what is this?)

Madison Unger

Retrieved from "http://52.214.119.220/wiki/index.php/User:Madison_Unger/Sandbox_1"

@@ Line 12: / Line 12: @@
 ACAT is a tetramer composed of a [http://en.wikipedia.org/wiki/Protein_dimer dimer] of a dimer, but is able to perform its function solely as a <scene name='87/877507/Dimer/1'>dimer</scene>. There are <scene name='87/877506/9_helices/5'>nine transmembrane helices</scene> in each domain which create a tunnel for the active site.  There are also three helices found on the intracellular side (IH1, IH2, and IH3) and one helix on the extracellular side (EH1). The active site contains three tunnels – the transmembrane tunnel for cholesterol entrance, the cytosolic tunnel for acyl-CoA entrance, and the lumen tunnel for cholesterol ester exit. ACAT also has an amino-terminal cytosolic domain (NTD) that is important for tetramerization of this protein.
 === Important Residues ===
-An important residue in the ACAT active site is His460, a [http://en.wikipedia.org/wiki/Histidine Histidine], which is located in the middle of the tunnels. It is thought that His460 is located on TM7 (Qian et al.). When converting to a cholesteryl ester, the <scene name='87/877507/His460/1'>His460</scene> acts as a catalytic base that deprotonates the cholesterol. Asn421 is another important residue in the reaction that is able to form a hydrogen bond with acyl-CoA for stabilization.
+An important residue in the ACAT active site is His460, a [http://en.wikipedia.org/wiki/Histidine Histidine], which is located in the middle of the tunnels. It is thought that His460 is located on TM7 (Qian et al.). When converting to a cholesteryl ester, the <scene name='87/877507/His460/1'>His460</scene> acts as a catalytic base that deprotonates the cholesterol. An [http://en.wikipedia.org/wiki/Asparagine asparagine] Asn421 is another important residue in the reaction that is able to form a [http://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bond] with acyl-CoA for stabilization.
 === Important Interactions ===
+Between the two protomers in each dimer, [http://en.wikipedia.org/wiki/Van_der_Waals_force van der waals] interactions occur between TM1 of one [http://en.wikipedia.org/wiki/Protomer protomer] and the lumenal TM6 and the cytosolic TM9 of the other protomer. The two dimers make limited contact within the membrane through an interface that is thought to be located between TM2, TM5, TM6 and IH2.
 == Proposed Mechanism ==
 [[Image:Acatmech1.png|400px|right|thumb|Figure 2: Proposed mechanism for ACAT]]