The FYRN and FYRC sequence motifs are two poorly characterized phenylalanine/
tyrosine-rich regions of around 50 and 100 amino acids, respectively, that are
found in a variety of chromatin-associated proteins [1,2,3,4]. They are
particularly common in histone H3K4 methyltransferases most notably in a
family of proteins that includes human mixed lineage leukemia (MLL) and the
Drosophila melanogaster protein trithorax. Both of these enzymes play a key
role in the epigenetic regulation of gene expression during development, and
the gene coding for MLL is frequently rearranged in infant and secondary
therapy-related acute leukemias. They are also found in transforming growth
factor β regulator 1 (TBRG1), a growth inhibitory protein induced in cells
undergoing arrest in response to DNA damage and transforming growth factor
(TGF)-β1. As TBRG1 has been shown to bind to both the tumor suppressor
p14ARF and MDM2, a key regulator of p53, it is also known as nuclear
interactor of ARF and MDM2 (NIAM). In most proteins, the FYRN and FYRC regions
are closely juxtaposed, however, in MLL and its homologues they are far
distant. To be fully active, MLL must be proteolytically processed by
taspase1, which cleaves the protein between the FYRN and FYRC regions . The
N-terminal and C-terminal fragments remain associated after proteolysis
apparently as a result of an interaction between the FYRN and FYRC regions.
How proteolytic processing regulates the activity of MLL is not known.
Intriguingly, the FYRN and FYRC motifs of a second family of histone H3K4
methyltransferases, represented by MLL2 and MLL4 in humans and TRR in
Drosophila melanogaster, are closely juxtaposed. FYRN and FYRC motifs are
found in association with modules that create or recognize histone
modifications in proteins from a wide range of eukaryotes, and it is likely
that in these proteins they have a conserved role related to some aspect of
chromatin biology .
The FYRN and FYRC regions are not separate independently folded domains, but
are components of a distinct protein module, The FYRN and FYRC motifs both
form part of a single folded module (the FYR domain), which adopts an α+
β fold consisting of a six-stranded antiparallel β-sheet followed by
four consecutive α-helices (see <PDB:2WZO>). The FYRN region corresponds
to β-strands 1-4 and their connecting loops, whereas the FYRC motif maps to
β-strand 5, β-strand 6 and helices α1 to α4. Most of the
conserved tyrosine and phenylalanine residues, after which these motifs are
named are involved in interactions that stabilize the fold. Proteins such as
MLL, in which the FYRN and FYRC regions are separated by hundreds of amino
acids, are expected to contain FYR domains with a large insertion between two
of the strands of the β-sheet (strands 4 and 5) .
The profiles we developed cover the entire FYRN and FYRC motifs.
July 2011 / First entry.
PROSITE methods (with tools and information) covered by this documentation:
Prasad R., Zhadanov A.B., Sedkov Y., Bullrich F., Druck T., Rallapalli R., Yano T., Alder H., Croce C.M., Huebner K., Mazo A., Canaani E.
Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax.
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