Tag Archives: Bri2

A research idea yours for the taking

Why would the gene for a protein contain a part which could form amyloid (the major component of the senile plaque of Alzheimer’s disease) and another part to prevent its formation. Therein lies a research idea, requiring no grant money, and free for you to pursue since I’ll be 80 this month and have no academic affiliation.

Bri2 (aka Integral TransMembrane protein 2B — ITM2B) is such a protein.  It is described in [ Proc. Natl. Acad. Sci. vol. 115 pp. E2752 – E2761 ’18 ] http://www.pnas.org/content/pnas/115/12/E2752.full.pdf.

As a former neurologist I was interested in the paper because two different mutations in the stop codon for Bri2 cause 2 familial forms of Alzheimer’s disease  Familial British Dementia (FBD) and Familial Danish Dementia (FDD).   So the mutated protein is longer at the carboxy terminal end.  And it is the extra amino acids which form the amyloid.

Lots of our proteins form amyloid when mutated, mutations in transthyretin cause familial amyloidotic polyneuropathy.  Amylin (Islet Amyloid Polypeptide — IAPP) is one of the most proficient amyloid formers.  Yet amylin is a protein found in the beta cell of the pancreas which releases insulin (actually in the same secretory granule containing insulin).

This is where Bri2 is thought to come in. It is also found in the pancreas.   Bri2 contains a 100 amino acid motif called BRICHOS  in its 266 amino acids which acts as a chaperone to prevent IAPP from forming amyloid (as it does in the pancreas of 90% of type II diabetics).

Even more interesting is the fact that the BRICHOS domain is found in 300 human genes, grouped into 12 distinct protein families.

Do these proteins also have segments which can form amyloid?  Are they like the amyloid in Bri2, in segments of the gene which can only be expressed if a stop codon is read through.  Nothing in the cell is perfect and how often readthrough occurs at stop codons isn’t known completely, but work is being done — Nucleic Acids Res. 2014 Aug 18; 42(14): 8928–8938.

I find it remarkable that the cause and the cure of a disease is found in the same protein.

Here’s the research proposal for you.  Look at the other 300 human genes containing the BRICHOS motif (itself just a beta sheet with alpha helices on either side) and see how many have sequences which can form amyloid.  There should be programs which predict the likelihood of an amino acid sequence forming amyloid.

It’s very hard to avoid teleology when thinking about cellular biochemistry and physiology.  It’s back to Aristotle where everything has a purpose and a design.  Clearly BRICHOS is being used for something or evolution/nature/natural selection/the creator would have long ago gotten rid of it.  Things that aren’t used tend to disappear in evolutionary time — witness the blind fish living in caves in Mexico that have essentially lost their eyes. The BRICHOS domain clearly hasn’t disappeared being present in over 1% of our proteins.

Suppose that many of the BRICHOS containing proteins have potential amyloid segments.  That would imply (to me at least) that the amyloid isn’t just junk that causes disease, but something with a cellular function. Finding out just what the function is would occupy several research groups for a long time.   This is also where you come in.  It may not pan out, but pathbreaking research is always a gamble when it isn’t stamp collecting.

 

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Amyloid again, again . . .

Big pharma has spent (and lost) several fortunes trying to attack the amyloid deposits of Alzheimer’s.  But like my late med school classmate’s book — “Why God Won’t Go Away” ==https://www.amazon.com/Why-God-Wont-Go-Away/dp/034544034X, amyloid won’t go away either.   It’s a bit oblique but some 300 of our proteins contain a 100 amino acid stretch called BRICHOS.  Why? Because it acts as a chaperone protein preventing proteins with a tendency to form amyloid from aggregating into fibrils.   The amino acids form a beta sheet surrounded front and back by a single alpha helix.

[ Proc. Natl. Acad. Sci. vol. 115 pp. E2752 – E2761 ’18 ] Discusses Bri2 (aka Integral Transmembrane protein 2B (ITM2B), a 266 amino acid type II transmembrane protein. Bri2 contains a carboxy terminal domain Bri23 released by proteolytic processing between amino acids #243 #244 by furinlike proteases. Different missense mutations at the stop codon of Bri2 cause extended carboxy terminal peptides called  Abri or Adan to be released by the proteases. Abri produces Familial British Dementia (FBD) and Adan produces Familial Danish Dementia (FDD). Both are associated with amyloid deposition in blood vessels, and amyloid plaques throughout the brain along with neurofibrillary tangles.

What is fascinating (to me) is that the cause and cure are both present in the same molecule Bri2 also contains a BRICHOS domain.  This implies (to me) that possibly the segment possibly forming amyloid is being used by the cell in some other fashion.

Bri2 is found in the beta cell of the pancreas (produces insulin).  The beta cell also produces Islet Amyloid PolyPeptide (IAPP  aka amylin ) one of the most potent amyloid forming proteins known.  Nonetheless the pancreas makes tons of it, and like insulin, is secreted by the beta cell in response to elevated blood glucose.  The present work shows that Bri2 is what keeps IAPP from forming amyloid.  The BRICHOS segment (amino acids #130 – #231) is released from Bri2 by ADAM10 (you don’t want to know what the acronym stands for).

How many of the 300 or so human proteins containing the BRICHOS domain also have amyloid forming segments.  If they do, this implies that the amyloid forming segments are doing something physiologically useful.