Gamma secretase: Difference between revisions
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== Structure of Gamma Secretase Complex == | == Structure of Gamma Secretase Complex == | ||
γ-secretase has been identified as an aspartyl protease accountable for cleaving over 90 integral membrane proteins after they have undergone ectodomain shedding. GS has been characterized as a high molecular weight complex that consists of four essential subunits in a 1:1:1:1 heterodimer<ref name= "carroll">DOI:10.1016/j.brainresbull.2016.04.019</ref>: <scene name='81/812869/Matilda_scene_2/2'>Presenilin (PS, PS1, or PS2)</scene>, <scene name='81/812869/Matilda_scene_1/6'>Nicastrin (NCT)</scene>, <scene name='81/812869/Matilda_scene_3/1'>Anterior Pharynx-Defective-1 (APH-1)</scene>, and Presenilin Enhancer-2 (PEN-2).<ref name= "thompson">DOI:10.1186/1756-6606-4-3</ref> | γ-secretase has been identified as an aspartyl protease accountable for cleaving over 90 integral membrane proteins after they have undergone ectodomain shedding. GS has been characterized as a high molecular weight complex that consists of four essential subunits in a 1:1:1:1 heterodimer<ref name= "carroll">DOI:10.1016/j.brainresbull.2016.04.019</ref>: <scene name='81/812869/Matilda_scene_2/2'>Presenilin (PS, PS1, or PS2)</scene>, <scene name='81/812869/Matilda_scene_1/6'>Nicastrin (NCT)</scene>, <scene name='81/812869/Matilda_scene_3/1'>Anterior Pharynx-Defective-1 (APH-1)</scene>, and <scene name='81/812869/Matilda_scene_4/1'>Presenilin Enhancer-2 (PEN-2)</scene>.<ref name= "thompson">DOI:10.1186/1756-6606-4-3</ref> | ||
PSs play a very significant role in AD and is considered a vital catalytic subunit in γ-secretase. PS are multi-transmembrane proteins with nine transmembrane helixes; it is assumed the amino-terminus is located in the cytosol while the carboxyl-terminus is exposed to the luminal/extracellular space. Functional PS requires endoproteolytic cleavage between TM6 and TM7 which generates a 27–28 kDa amino-terminal fragment (NTF) and a 16–17 kDa carboxyl-terminal fragment (CTF). <ref name="zhang" /> The two aspartyl residues in PS1 and PS2 ('''D257''' in TM 6 and at '''D385''' in TM 7) play crucial roles in intramembranous cleavage and AD plaque formation; substitutions of these residues reduces cleavage of APP and Notch1 proteins.<ref name= "o'brien">DOI:10.1146/annurev-neuro-061010-113613</ref> PS, NTF, and CTF bind to form stable and active PS heterodimers at a 1:1 stoichiometry. <ref name="zhang" /> | PSs play a very significant role in AD and is considered a vital catalytic subunit in γ-secretase. PS are multi-transmembrane proteins with nine transmembrane helixes; it is assumed the amino-terminus is located in the cytosol while the carboxyl-terminus is exposed to the luminal/extracellular space. Functional PS requires endoproteolytic cleavage between TM6 and TM7 which generates a 27–28 kDa amino-terminal fragment (NTF) and a 16–17 kDa carboxyl-terminal fragment (CTF). <ref name="zhang" /> The two aspartyl residues in PS1 and PS2 ('''D257''' in TM 6 and at '''D385''' in TM 7) play crucial roles in intramembranous cleavage and AD plaque formation; substitutions of these residues reduces cleavage of APP and Notch1 proteins.<ref name= "o'brien">DOI:10.1146/annurev-neuro-061010-113613</ref> PS, NTF, and CTF bind to form stable and active PS heterodimers at a 1:1 stoichiometry. <ref name="zhang" /> | ||
The remaining three subunits (NCT, APH-1, PEN-2) help with stabilizing GS by forming a mature enzyme. NCT contains a large extracellular (or ectodomain) domain, transmembrane helix, and smaller cytoplasmic domain.<ref name= "carroll" />The ectodomain of NCT recognizes and binds to the amino-terminal stubs of previously cleaved transmembrane proteins. APH-1 aids the formation of a pre-complex, which interacts with PS1 or PS2<ref name= "o'brien" />; it contains two different isoforms from two paralogous genes on chromosomes 1 '''(APH-1A)''' and 15 '''(APH-1B)'''. While PEN-2 works in enzyme maturation<ref name= "carroll" />; it enters the formed complex to initiate the cleavage of PS1 or PS2 to form an N-terminal 28-kDa fragment and a C-terminal 18-kDa fragment, both APH-1 and PEN-2 are critical to the γ-secretase complex.<ref name= "o'brien" /> The γ-secretase complex has a molecular weight of approximately 170 kDa, with an additional 30–70 kDa derived from NCT glycosylation, reaching a total size of about 230 kDa with 19 TMs.<ref name= "zhang" /> | The remaining three subunits (NCT, APH-1, PEN-2) help with stabilizing GS by forming a mature enzyme. NCT contains a large extracellular (or ectodomain) domain, transmembrane helix, and smaller cytoplasmic domain.<ref name= "carroll" />The ectodomain of NCT recognizes and binds to the amino-terminal stubs of previously cleaved transmembrane proteins. APH-1 aids the formation of a pre-complex, which interacts with PS1 or PS2<ref name= "o'brien" />; it contains two different isoforms from two paralogous genes on chromosomes 1 '''(APH-1A)''' and 15 '''(APH-1B)'''. While PEN-2 works in enzyme maturation<ref name= "carroll" />; it enters the formed complex to initiate the cleavage of PS1 or PS2 to form an N-terminal 28-kDa fragment and a C-terminal 18-kDa fragment, both APH-1 and PEN-2 are critical to the γ-secretase complex.<ref name= "o'brien" /> The γ-secretase complex has a molecular weight of approximately 170 kDa, with an additional 30–70 kDa derived from NCT glycosylation, reaching a total size of about 230 kDa with 19 TMs.<ref name= "zhang" /> | ||
