Tag Archives: Endoplasmic Reticulum aminopeptidase associated with Antigen Processing

How a chemical measuring stick actually works

The immune system knows something is up when a foreign peptide fragment is presented to it.  Here’s the hand holding the peptide — https://www.researchgate.net/figure/Overall-structure-of-HLA-peptide-complex_fig1_26490512.

There it sits, lying on top of a bed of beta sheets, with two side rails of alpha helices.  Proteins are big, way too big to fit into the hand, so the fragments must be chopped up into peptides no longer than 9 amino acids long (see the picture of it lying in state).

So the class assignment for today is to figure out how to design a protein which takes peptides from 10 – 16 amino acids long, and shortens them to 9 amino acids.

Obviously a trick question, because the actual amino acids making up the peptide don’t really matter much.  So somehow the protein is reacting to length rather than chemistry.

Tricky no?

ERAP1 (Endoplasmic Reticulum aminopeptidase associated with Antigen Processing has figured it out [ Proc. Natl. Acad. Sci. vol. 116 pp. 22709 – 22715 ’19 ].  It is a huge protein (948 amino acids) with four domains forming a large cavity (which it must have to accomodate a 19 amino acid paptide).  The peptide is chopped up from the amino terminal, stopping when the length reaches 9 amino acids.  The active site is at one end of the cavity, and at the other end there is a site which looks like it should cleave the carboxyterminal amino acid, but it doesn’t because the site is inactive.  However, even catalytically inactive enzymatic sites have enough structure left so they bind the substrate.

So binding of the carboxy terminal amino acid to the back site causes conformational changes transmitted through various alpha helices to the active enzyme at the other end.  It munches away removing amino acid after amino acid until the peptide gets short enough (translation 9 amino acids) so that it doesn’t push on the back site.

Incredibly clever, even though it hurts me as a chemist to see the enzyme essentially ignoring the chemistry of its substrate.

I far prefer this to politics where data is ignored.  Two examples

l. From a review of a book by Paul Krugman in the Jan/Feb 2020 Atlantic

“Krugman is substantively correct on just about every topic he addresses.” Yes except Peak Oil in 2010, Stock Market collapse in Nov 2016 and the coming recession in an article April 2019

2. Former Secretary of Labor Robert Reich in the Guardian 22 Dec ’19 — “How Trump has betrayed the working class” — by employing them and raising their wages no doubt.