Molecular Biology and Evolution, Vol 15, 665-682, Copyright © 1998 by Society for Molecular Biology and Evolution
S Garcia-Vallve and J Palau
We studied a human protein paralog cluster formed by 38 nonredundant
sequences taken from the Swiss-Prot database and its supplement, TrEMBL.
These sequences include nuclear receptors, nuclear-receptor factors and
nuclear-receptor-like orphans. Working separately with both the central
cysteine-rich DNA-binding domain and the carboxy-terminal ligand-binding
domain, we performed multialignment analyses that included drawings of
paralog trees. Our results show that the cluster is highly multibranched,
with considerable differences in the amino acid sequence in the
ligand-binding domain (LBD), and 17 proximal subbranches which are
identifiable and fully coincident when independent trees from both domains
are compared. We identified the six recently proposed subfamilies as groups
of neighboring clusters in the LBD paralog tree. We found similarities of
80%-100% for the N-terminal transactivation domain among mammalian ortholog
receptors, as well as some paralog resemblances within diverse subbranches.
Our studies suggest that during the evolutionary process, the three domains
were assembled in a modular fashion with a nonshuffled modular fusion of
the LBD. We used the EMBL server PredictProtein to make secondary-structure
predictions for all 38 LBD subsequences. Amino acid residues in the
multialigned homologous domains--taking the beginning of helix H3 of the
human retinoic acid receptor-gamma as the initial point of reference--were
substituted with H or E, which identify residues predicted to be helical or
extended, respectively. The result was a secondary structure multialignment
with the surprising feature that the prediction follows a canonical pattern
of alignable alpha-helices with some short extended elements in between,
despite the fact that a number of subsequences resemble each other by less
than 25% in terms of the similarity index. We also identified the presence
of a binary patterning in all of the predicted helices that were conserved
throughout the 38-sequence sample. Our results fit well with a recently
proposed evolutionary model that combines protein secondary structure and
amino acid replacement. We propose a new hypothesis for molecular
evolution, in which chaperones--acting as an endogenous cellular device for
selection--play a crucial role in preserving protein secondary structure.
ORIGINAL ARTICLE
Nuclear receptors, nuclear-receptor factors, and nuclear-receptor-like orphans form a large paralog cluster in Homo sapiens
Departament de Bioquimica i Biotecnologia, Universitat Rovira i Virgili, Catalonia, Spain.
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