How much homology is needed to function?

Tue Jun 1 12:55:34 EST 1993

Organization: Temple University
References: <16BDA853C.SHICKLEY at VM.TEMPLE.EDU> <1u8m0u$qn at>
X-Newsreader: NNR/VM S_1.3.2

In article <1u8m0u$qn at>
mhollowa at (Michael Holloway) writes:
>>Organization: Temple University
>>X-Newsreader: NNR/VM S_1.3.2
>>My question is: Has anyone else seen evidence of small regions of
>>homology which have "actual" functional significance? How much
>>conservation is necessary to carry out a job for a protein? We
>>have some evidence that regional homologies, albeit small, can
>>confer suprising proerties on a protein--if one looks for them.
>We just had a symposium on protein-protein interactions in transcriptional
>interactions here and comparing homologies of helix-loop-helix domains
>came up several times during different talks.  In comparing the HLA domains
>of POU-homeo domains, aligning the alpha helixes was needed before the
>homology of three residues could be seen (if I recall correctly).  In other
>words, you had to have an hypothesis about the function of putative tertiary
>structure before you could see any homology.  The homology is just too small
>to have an algorithm just spit it out at you.  Winship Herr was comparing
>the lambda repressor with the POU-homeo domains of Oct1 and 2 and with
>Herpes VP-16.
Looking for the 3D or tertiary homologies IS a problem. An example of
what we found: We examined the primary structure of an anti-haloperidol
antibody sequence and compared it to known "dopamine"-related proteins
hoping to find a "dopamine" binding motif. What we found instead was
an apparent haloperidol binding motif on muscarinic cholinergic receptors.
We hypothesized that this might be related to haloperidol binding to
muscarinic receptors, and possibly the side-effects associated with
the use of this antipsychotic drug (many  of the SE's being cholinergic).
Well we found an apparently novel allosteric binding site for haloperidol
on the muscarinic receptors (m-2 anyway) which actually appeared to
ENHANCE the binding of other drugs. We've submitted this for publication
and are awaiting reviews, but it all started with examining relatively
SMALL areas of homology on primary sequences. The "patches" of homology
did show up on helical regions which probably need to be aligned for
the binding to occur, but it was suprising to me that something functional
actually popped out of the primary sequence homology studies.
My feeling is now that some homologies, albiet small or with low overall
scores, may have an interesting function which may be uncovered with some
experimentation. We are looking now at viral hijacking of functional
proteins with a subsequent destruction of homologous SELF protein by
a "limited engagement" immune response (ie, transient autoimmune resp.).
Timothy J. Shickley, Ph.D.   Director, Neurourology
Departments of Urology and Anatomy/Cell Biology
Temple University School of Medicine
3400 North Broad St.
Philadelphia, PA 19140
(VOICE/DATA) 215-221-8966; (VOICE)215-221-4567; (FAX)215-221-4565
INTERNET: shickley at     BITNET: shickley at templevm.bitnet
ICBM: 39 57 08N
      75 09 51W

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