User:Daniel Mulawa/Sandbox 1 - Revision history

Daniel Mulawa at 21:31, 30 March 2020

Daniel Mulawa — Mon, 30 Mar 2020 21:31:14 GMT

←Older revision		Revision as of 21:31, 30 March 2020
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	='''Gamma Secretase'''=		='''Gamma Secretase'''=
-	~~<scene name='83/837256/Practice_scene_1/2'>Text To Be Displayed</scene>=''Human'' Gamma Secretase=~~	+	<StructureSection load='5FN2' size='350' frame='true' side='right' caption='Human Gamma Secretase Basic Structure.' scene=’’>
-	<StructureSection load='~~5A63~~' size='350' frame='true' side='right' caption='Gamma Secretase ~~5A63~~' scene=~~'83/837256/Practice_scene_1/1'~~>	+
	=Gamma Secretase=		=Gamma Secretase=

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	Anterior pharynx-defective 1 (APH-1) serves as a scaffold for anchoring and supporting the flexible conformational changes of PS1		Anterior pharynx-defective 1 (APH-1) serves as a scaffold for anchoring and supporting the flexible conformational changes of PS1
	Activation of the active site is dependent on the binding of Presenilin enhancer 2 (PEN-2). PEN-2 is also important in maturation of the enzyme.		Activation of the active site is dependent on the binding of Presenilin enhancer 2 (PEN-2). PEN-2 is also important in maturation of the enzyme.
-
-	[[Image:Ribbon structure of whole.png\|350 px\|right\|thumb\|Figure 1]]
-	[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]
-	===practice===
-
-	<scene name='83/837256/Practice_scene_1/2'>practice 2</scene>
-
-


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	===Active Site===		===Active Site===
-	The active site is located between TM6 and TM7 of the PS1 subunit, which is mainly hydrophilic and disordered. Each of these transmembrane helices has an aspartate residue, ~~Asp257~~ and ~~Asp385~~, which are located approximately 10.6 A˚ apart when inactive.	+	[[Image:Asp with Pal labeled.png\|300 px\|right\|thumb\|Active Site of Gamma Secretase]]
		+	The <scene name='83/832945/Active_site/1'>active site</scene> is located between TM6 and TM7 of the PS1 subunit, which is mainly hydrophilic and disordered. Each of these transmembrane helices has an aspartate residue, <scene name='83/832945/Asp_257_and_asp_385/1'>Asp 257 and Asp 385</scene>, which are located approximately 10.6 A˚ apart when inactive.<ref name="Bai">PMID:26280335</ref> The PAL sequence of <scene name='83/832945/Pal_sequence/1'>Pro433, Ala434, and Leu435</scene> is in close proximity with the catalytic aspartates and is important to substrate recognition. Gamma secretase becomes active upon substrate binding, when TM2 and TM6 each rotate about 15 degrees to more closely associate and the two Asp residues hydrogen bond to each other during catalysis. Asp257 and Asp385 are located 6–7 Å away from the scissile peptide bond of the substrate.
		+

	==Relevance==		==Relevance==
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	Important to look at differences between substrates		Important to look at differences between substrates

-

		+	</StructureSection>

-	</StructureSection>
	== References ==		== References ==
-	1.Bai X, Yan C, Guanghui Yang, et al. 2015. An atomic structure of human γ-secretase. Nature. 525:212-217.
-	2.Carroll CM, and Li YM. 2016. Physiological and pathological roles of the γ-secretase complex. Brain research bulletin. 126:199-206.
-	3.Yang G, Zhou R, Shi Y. 2017. Cryo-EM structures of human γ-secretase. Current Opinion in Structural Biology. 46:55–64.
-	4.Yang G, Zhou R, Zhou Q, et al. 2019. Structural basis of Notch recognition by human γ-secretase. Nature. 565: 192-197.
-	5.Zhou R, Yang G, Guo X, et al. 2019. Recognition of the amyloid precursor protein by human γ-secretase. Science. 363:1-8.
	<references/>		<references/>

	==Student Contributors==		==Student Contributors==
	Layla Wisser		Layla Wisser
		+
	Daniel Mulawa		Daniel Mulawa

Daniel Mulawa at 20:41, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:41:06 GMT

←Older revision		Revision as of 20:41, 24 March 2020
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	===Overall Structure===		===Overall Structure===
-	20 transmembrane components (TMs)	+	Γ-secretase is composed of 20 transmembrane components (TMs) and has 4 subunits: Nicastran, Anterior Pharynx-defective 1, Presenilin, and Presenilin Enhancer 2. These subunits are stabilized by hydrophobic interactions and 4 phosphatidylcholines.These phosphatidylcholines have interfaces between: PS1 and PEN-2, APH-1 and PS1, APH-1 and NCT.
-	4 subunits	+	Nicastrin (NCT) has a large extracellular domain and 1 TM. It is important to substrate recognition and binding.
-	Nicastran ~~(NCT)~~,Anterior ~~pharynx~~-defective 1 ~~(APH-1)~~, Presenilin ~~(PS1)~~, Presenilin ~~enhancer~~ 2 ~~(PEN-2), and4~~ phosphatidylcholines ~~stabilize structure (interface~~ between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)	+	Presenilin (PS1) serves as the active site of the protease and contains 9 TMs, each varying in length. The site of autocatalytic cleavage is located between TM6 and TM7 in PS1 and major conformational changes take place in this subunit upon substrate binding.
		+	Anterior pharynx-defective 1 (APH-1) serves as a scaffold for anchoring and supporting the flexible conformational changes of PS1
		+	Activation of the active site is dependent on the binding of Presenilin enhancer 2 (PEN-2). PEN-2 is also important in maturation of the enzyme.
		+
	[[Image:Ribbon structure of whole.png\|350 px\|right\|thumb\|Figure 1]]		[[Image:Ribbon structure of whole.png\|350 px\|right\|thumb\|Figure 1]]
	[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]		[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]
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	===Active Site===		===Active Site===
		+	The active site is located between TM6 and TM7 of the PS1 subunit, which is mainly hydrophilic and disordered. Each of these transmembrane helices has an aspartate residue, Asp257 and Asp385, which are located approximately 10.6 A˚ apart when inactive.

	==Relevance==		==Relevance==

Daniel Mulawa at 20:37, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:37:08 GMT

←Older revision		Revision as of 20:37, 24 March 2020
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	===Substrate Structure===		===Substrate Structure===
	Though gamma secretase has multiple substrates, the substrate of main concern is called Amyloid Precursor Protein (APP). APP is composed of an N-terminal loop, a transmembrane (TM) helix, and a C-terminal β-strand. The uses lateral diffusion as a mechanism of entry into the enzyme, and once in place, the TM helix is anchored by hydrogen bonds. In order to differentiate substrates, the β-strand is often the main point of identification for the enzyme. After this, the helix undergoes unwinding and the process of catalysis can begin.		Though gamma secretase has multiple substrates, the substrate of main concern is called Amyloid Precursor Protein (APP). APP is composed of an N-terminal loop, a transmembrane (TM) helix, and a C-terminal β-strand. The uses lateral diffusion as a mechanism of entry into the enzyme, and once in place, the TM helix is anchored by hydrogen bonds. In order to differentiate substrates, the β-strand is often the main point of identification for the enzyme. After this, the helix undergoes unwinding and the process of catalysis can begin.
-	TM helix anchored by hydrogen bonds
-	Unwinding model
-	used for substrate recognition

	===Lid Complex===		===Lid Complex===

Daniel Mulawa at 20:36, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:36:14 GMT

←Older revision		Revision as of 20:36, 24 March 2020
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	== Structural highlights ==		== Structural highlights ==
	===Substrate Structure===		===Substrate Structure===
-	~~Made~~ of an N-terminal loop, a transmembrane helix, and a C-terminal β-strand	+	Though gamma secretase has multiple substrates, the substrate of main concern is called Amyloid Precursor Protein (APP). APP is composed of an N-terminal loop, a transmembrane (TM) helix, and a C-terminal β-strand. The uses lateral diffusion as a mechanism of entry into the enzyme, and once in place, the TM helix is anchored by hydrogen bonds. In order to differentiate substrates, the β-strand is often the main point of identification for the enzyme. After this, the helix undergoes unwinding and the process of catalysis can begin.
-	~~Lateral~~ diffusion to ~~enter~~ enzyme	+
	TM helix anchored by hydrogen bonds		TM helix anchored by hydrogen bonds
	Unwinding model		Unwinding model
-	~~β-strand~~ used for substrate recognition	+	used for substrate recognition

	===Lid Complex===		===Lid Complex===
-		+	Lid is the first point of entry and recognition for the substrate.

	===Active Site===		===Active Site===

Daniel Mulawa at 20:30, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:30:12 GMT

←Older revision		Revision as of 20:30, 24 March 2020
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	===Background===		===Background===
-	Gamma Secretase is a transmembrane aspartate protease	+	Gamma Secretase is a transmembrane aspartate protease. It catalyzes peptide bond hydrolysis of type I integral membrane proteins such as Notch, APP, and various other substrates. It recognizes and catalyzes the reaction with its substrate using 3 residue segments. These substrates generate amyloid-β (Aβ). This product is important for various neural processes, and it is well known for its Implications with Alzheimer’s disease (AD). This has made gamma secretase a popular drug target, specifically using gamma secretase (GS) inhibitors. However, due to the nature of gamma secretase having various neural functions, there are dangerous side effects when it is inhibited.
-	~~Catalyzes~~ peptide bond hydrolysis of type I integral membrane proteins	+
-	~~Such~~ as Notch, APP, and various other substrates	+
-	3 residue segments~~; allow binding and cleavage~~	+
-	~~Generates~~ amyloid-β (Aβ)	+
-	~~Important~~ for neural processes	+
-	Implications with Alzheimer’s disease (AD)	+
-	~~Drug~~ target	+
-	GS inhibitors	+
-	~~Dangerous~~ side effects	+
	===Overall Structure===		===Overall Structure===
	20 transmembrane components (TMs)		20 transmembrane components (TMs)

Daniel Mulawa at 20:24, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:24:37 GMT

←Older revision		Revision as of 20:24, 24 March 2020
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	4 subunits		4 subunits
	Nicastran (NCT),Anterior pharynx-defective 1 (APH-1), Presenilin (PS1), Presenilin enhancer 2 (PEN-2), and4 phosphatidylcholines stabilize structure (interface between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)		Nicastran (NCT),Anterior pharynx-defective 1 (APH-1), Presenilin (PS1), Presenilin enhancer 2 (PEN-2), and4 phosphatidylcholines stabilize structure (interface between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)
-	[[Image:Ribbon structure of whole.png\|~~300~~ px\|right\|thumb\|Figure 1]]	+	[[Image:Ribbon structure of whole.png\|350 px\|right\|thumb\|Figure 1]]
	[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]		[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]
	===practice===		===practice===
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	</StructureSection>		</StructureSection>
	== References ==		== References ==
		+	1.Bai X, Yan C, Guanghui Yang, et al. 2015. An atomic structure of human γ-secretase. Nature. 525:212-217.
		+	2.Carroll CM, and Li YM. 2016. Physiological and pathological roles of the γ-secretase complex. Brain research bulletin. 126:199-206.
		+	3.Yang G, Zhou R, Shi Y. 2017. Cryo-EM structures of human γ-secretase. Current Opinion in Structural Biology. 46:55–64.
		+	4.Yang G, Zhou R, Zhou Q, et al. 2019. Structural basis of Notch recognition by human γ-secretase. Nature. 565: 192-197.
		+	5.Zhou R, Yang G, Guo X, et al. 2019. Recognition of the amyloid precursor protein by human γ-secretase. Science. 363:1-8.
	<references/>		<references/>

Daniel Mulawa at 20:20, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:20:13 GMT

←Older revision		Revision as of 20:20, 24 March 2020
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	4 subunits		4 subunits
	Nicastran (NCT),Anterior pharynx-defective 1 (APH-1), Presenilin (PS1), Presenilin enhancer 2 (PEN-2), and4 phosphatidylcholines stabilize structure (interface between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)		Nicastran (NCT),Anterior pharynx-defective 1 (APH-1), Presenilin (PS1), Presenilin enhancer 2 (PEN-2), and4 phosphatidylcholines stabilize structure (interface between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)
-	[[Image:Ribbon structure of whole.png\|~~400~~ px\|right\|thumb\|Figure 1]]	+	[[Image:Ribbon structure of whole.png\|300 px\|right\|thumb\|Figure 1]]
	[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]		[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]
	===practice===		===practice===
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	===Lid Complex===		===Lid Complex===
-	~~[[Image:7.png]]~~	+
		+
	===Active Site===		===Active Site===

-	== Relevance ~~and Disease~~ ==	+	==Relevance==
	APP build up leads to Amyloid plaques in brain		APP build up leads to Amyloid plaques in brain
	Inhibition of γ-secretase could be potential AD treatment		Inhibition of γ-secretase could be potential AD treatment

Daniel Mulawa at 20:14, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:14:12 GMT

←Older revision		Revision as of 20:14, 24 March 2020
Line 39:		Line 39:

	===Lid Complex===		===Lid Complex===
		+	[[Image:7.png]]
	===Active Site===		===Active Site===

Daniel Mulawa at 20:10, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:10:20 GMT

←Older revision		Revision as of 20:10, 24 March 2020
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	==Introduction==		==Introduction==
-	~~[[Image:Ribbon structure of whole.png\|400 px\|right\|thumb\|Figure 1]]~~	+
-	~~[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]~~	+
	===Background===		===Background===
	Gamma Secretase is a transmembrane aspartate protease		Gamma Secretase is a transmembrane aspartate protease
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	4 subunits		4 subunits
	Nicastran (NCT),Anterior pharynx-defective 1 (APH-1), Presenilin (PS1), Presenilin enhancer 2 (PEN-2), and4 phosphatidylcholines stabilize structure (interface between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)		Nicastran (NCT),Anterior pharynx-defective 1 (APH-1), Presenilin (PS1), Presenilin enhancer 2 (PEN-2), and4 phosphatidylcholines stabilize structure (interface between PS1 and PEN-2; APH-1 and PS1; APH-1 and NCT)
-		+	[[Image:Ribbon structure of whole.png\|400 px\|right\|thumb\|Figure 1]]
		+	[http://http://proteopedia.org/wiki/index.php/5a63 5A63 Article]
	===practice===		===practice===

Daniel Mulawa at 20:05, 24 March 2020

Daniel Mulawa — Tue, 24 Mar 2020 20:05:26 GMT

←Older revision		Revision as of 20:05, 24 March 2020
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	== Structural highlights ==		== Structural highlights ==
	===Substrate Structure===		===Substrate Structure===
		+	Made of an N-terminal loop, a transmembrane helix, and a C-terminal β-strand
		+	Lateral diffusion to enter enzyme
		+	TM helix anchored by hydrogen bonds
		+	Unwinding model
		+	β-strand used for substrate recognition
		+
	===Lid Complex===		===Lid Complex===
	===Active Site===		===Active Site===
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-	This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">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.

	</StructureSection>		</StructureSection>
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	==Student Contributors==		==Student Contributors==
	Layla Wisser		Layla Wisser
		+	Daniel Mulawa