Role of the ubiquitin-like modifier FAT10 in protein degradation and ...
Role of the ubiquitin-like modifier FAT10 in protein degradation and ...
Role of the ubiquitin-like modifier FAT10 in protein degradation and ...
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Introduction<br />
Chapter 1<br />
Ubiquit<strong>in</strong>, a small prote<strong>in</strong> <strong>of</strong> 76 am<strong>in</strong>o acids is one <strong>of</strong> <strong>the</strong> most conserved pro-<br />
te<strong>in</strong>s known <strong>and</strong> has been found <strong>in</strong> all eukaryotic cells studied. It is essen-<br />
tial for a variety <strong>of</strong> cellular processes, <strong>in</strong>clud<strong>in</strong>g <strong>degradation</strong>, cell-cycle regula-<br />
tion, DNA repair, stress response, embryogenesis, apoptosis, signal transduc-<br />
tion, <strong>and</strong> transmembrane- <strong>and</strong> vesicular transport. (Pickart, 2001; Hicke, 2001;<br />
Jesenberger <strong>and</strong> Jentsch, 2002; Lai, 2002; Ma <strong>and</strong> Hendershot, 2001; Koepp<br />
et al., 1999). Throughout <strong>the</strong> past years, a family <strong>of</strong> prote<strong>in</strong>s conta<strong>in</strong><strong>in</strong>g struc-<br />
tural motives related to <strong>ubiquit<strong>in</strong></strong> has been described which can be grouped<br />
<strong>in</strong>to <strong>the</strong> <strong>ubiquit<strong>in</strong></strong>-<strong>like</strong> <strong>modifier</strong>s <strong>and</strong> <strong>the</strong> <strong>ubiquit<strong>in</strong></strong>-doma<strong>in</strong> prote<strong>in</strong>s (Jentsch <strong>and</strong><br />
Pyrowolakis, 2000). The <strong>ubiquit<strong>in</strong></strong>-<strong>like</strong> <strong>modifier</strong>s have substantial sequence or<br />
structural homology to <strong>ubiquit<strong>in</strong></strong> <strong>and</strong> form covalent conjugates with <strong>the</strong>ir target<br />
prote<strong>in</strong>s. However, un<strong>like</strong> <strong>ubiquit<strong>in</strong></strong>, which can form large polymeric conjugates,<br />
usually only monomeric modifications are observed. As is <strong>the</strong> case for ubiqui-<br />
t<strong>in</strong>, a C-term<strong>in</strong>al diglyc<strong>in</strong>e motif is essential for conjugation <strong>of</strong> most <strong>modifier</strong>s to<br />
<strong>the</strong>ir target prote<strong>in</strong>s (Yeh et al., 2000). Prom<strong>in</strong>ent members <strong>of</strong> this group <strong>in</strong>clude<br />
SUMO-1, which serves several functions <strong>in</strong>clud<strong>in</strong>g nuclear transport <strong>and</strong> bud-<br />
d<strong>in</strong>g, (Matunis et al., 1996; Müller et al., 2001), NEDD8, which regulates SCF<br />
<strong>ubiquit<strong>in</strong></strong>-ligases via cull<strong>in</strong> modification (Osaka et al., 2000), ISG15, which plays<br />
a role <strong>in</strong> <strong>in</strong>nate immunity <strong>and</strong> <strong>in</strong> <strong>the</strong> response to alpha <strong>in</strong>terferon, (Ritchie et al.,<br />
2004; Kim et al., 2005) <strong>and</strong> <strong>FAT10</strong>, which is <strong>in</strong>ducible with gamma <strong>in</strong>terferon<br />
(IFN)-γ <strong>and</strong> tumour necrosis factor alpha (TNF)-α (Raasi et al., 1999; Liu et al.,<br />
1999), <strong>and</strong> has been shown to cause apoptosis upon ectopic expression (Raasi<br />
et al., 2001).<br />
The <strong>ubiquit<strong>in</strong></strong>-<strong>like</strong> prote<strong>in</strong> <strong>FAT10</strong> consists <strong>of</strong> two UBL doma<strong>in</strong>s <strong>in</strong> a head to tail<br />
formation, which are about 29% <strong>and</strong> 36% identical to <strong>ubiquit<strong>in</strong></strong>, respectively. Sev-<br />
eral key features <strong>of</strong> <strong>ubiquit<strong>in</strong></strong>, <strong>like</strong> <strong>the</strong> lys<strong>in</strong>e residues 48, 63, <strong>and</strong> 29, which are<br />
required for poly<strong>ubiquit<strong>in</strong></strong> cha<strong>in</strong> formation, are conserved <strong>in</strong> both UBL-doma<strong>in</strong>s<br />
(Fan et al., 1996). Its C-term<strong>in</strong>us bears a free diglyc<strong>in</strong>e motif, which is neces-<br />
sary for <strong>the</strong> conjugation to so far unidentified target prote<strong>in</strong>s (Raasi et al., 2001).<br />
Like <strong>ubiquit<strong>in</strong></strong> (Johnson et al., 1992), <strong>FAT10</strong> causes rapid <strong>degradation</strong> <strong>of</strong> long-<br />
lived prote<strong>in</strong>s when fused to <strong>the</strong> N-term<strong>in</strong>us (Hipp et al., 2005). However, un<strong>like</strong><br />
<strong>ubiquit<strong>in</strong></strong>, which is recycled from <strong>the</strong> degraded target prote<strong>in</strong>s, <strong>FAT10</strong> is digested<br />
along with its substrates. <strong>FAT10</strong> thus has a relatively short half life (Hipp et al.,<br />
2004), which decreases dramatically by coexpression <strong>of</strong> a member <strong>of</strong> <strong>the</strong> group<br />
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