Biology Reference
In-Depth Information
serpins share a common ancestor some 500 Myrs ago (Bao
et al
., 1987) and include
1-antichymotrypsin (
AACT
; 14q32),
heparin cofactor II (
HCF2
; 22q11), antithrombin (
AT3
; 1q23),
1-proteinase inhibitor (
PI
; 14q32),
2-antiplasmin
(
PLI
; 17p13), pigment epithelium-derived factor (
PEDF
; 17p13), C1-inhibitor
(
C1I
; 11q11-q13), protein C inhibitor (
PCI
; 14q32) and plasminogen activator
inhibitors 1 and 2 (
PAI1
, 7q21-q22;
PAI2
, 18q21.3). Other less well characterized
mammalian serpins include cytoplasmic antiproteinase 2 (
PI8
; 18q21.3), maspin
(
PI5
; 18q21.3), nexin (
PI7
; 2q33-q35), kallistatin (
PI4
; 14), neuroserpin (
PI12
;
3q26). Thus, serpin gene clusters are found at 14q32, 17p13 and 18q21.3 in the
human genome.
Not all serpins act as protease inhibitors. Thus, angiotensinogen (
AGT
; 1q41)
and corticosteroid-binding globulin (
CBG
; 14q32) act as blood pressure regula-
tory hormones whilst ovalbumin functions as an avian egg storage protein.
Although there is no ovalbumin gene in the human genome, there are several
genes encoding ovalbumin-like serpins (ov-serpins) which are clustered either on
18q21.3 (
PI10
,
SCCA1
,
SCCA2
) or 6p25 (
PI2
,
PI6
,
PI9
). The ov-serpins on chro-
mosome 6 share more amino acid sequence identity with one another than they
do with their chromosome 18 counterparts with the exception of PI8 (Bartuski
et
al
., 1997). By contrast, most of the chromosome 18 ov-serpins share greater
sequence identity with a chromosome 6 ov-serpin than with each other. To
account for these observations, Bartuski
et al
. (1997) proposed that the 6p25 loci
arose first and then gave rise to the chromosome 18 cluster.
Dendrograms derived from comparisons of serpin nucleotide and amino acid
sequences and of intron positions differ significantly (Wright, 1993). The
exon/intron organization of extant serpin genes is therefore unlikely to be explic-
able simply in terms of the loss of introns from a large primordial gene. Wright
(1993) proposed that the serpin gene family arose from an early recombination
event which fused the amino and carboxyl domains. The subsequent insertion of
sequence (possibly intronic) served to create
-sheet A and stabilized the new
structure. Few of the introns demarcate regions of secondary or tertiary structure
and further insertions, deletions and migrations of introns must have occurred.
Substrate specificity manifested by the serpin is determined, at least in part, by
the P1 residue of the bait loop which contains Met or Val for elastase, Lys for
trypsin, Leu for chymotrypsin and Arg for thrombin. After gene duplication,
divergence in terms of substrate specificity has been very rapid and has resulted
from 'accelerated evolution' of the reactive center region (Hill and Hastie, 1987).
This rapid evolution is thought to have taken place by a combination of mecha-
nisms, from genetic drift to gene conversion to positive Darwinian selection
(Graur and Li, 1988; Hill and Hastie, 1987; Ohta, 1994).
Zinc finger genes.
The term 'zinc finger' refers to a 28 amino acid sequence motif
which binds zinc ions thereby stabilizing the structure of a small DNA-binding
domain (El-Baradi and Pieler, 1991). It has been estimated that between 300 and 700
human genes encode zinc finger-containing proteins (Hoovers
et al.
, 1992). Most of
these proteins belong to the
Kruppel
-type family and act as transcription factors (El-
Baradi and Pieler, 1991). Zinc finger proteins often contain multiple zinc finger
motifs, the number varying from between 2 and 37 (Klug and Schwabe, 1995).
