2 Posttranslational Chemical Modification of Proteins ROSA U Y 3 M Central Research Lab, St. Paul, MN 55101
Downloaded by FUDAN UNIV on March 7, 2017 | http://pubs.acs.org Publication Date: May 28, 1980 | doi: 10.1021/bk-1980-0123.ch002
FINN WOLD Department of Biochemistry, University of Minnesota, St. Paul, MN 55108
It is now well established that the poly-(amino acid) chains assembled from the 20 amino acids specified by the genetic code undergo extensive processing before the biologically active final products of protein biosynthesis are obtained. Most of this processing involves covalent modification, either by making or breaking peptide bonds or by derivatizing the free α-NH or αCOOH groups or the amino acid side chains. These covalent modi fications, which may take place immediately after the formation of the amino acyl-tRNA, during the elongation of the nascent polypeptide chain on the polysomes or after the polymer has been completed and is being transported through intracellular or extracellular space, can a l l be considered as posttranslational modifications. A recent refinement on this terminology has been to distinguish between cotranslational modifications (all events taking place during polymerization on the polysomes) and posttranslational modification (all events after the release of the protein precursor from the polysomes). In this system of designation, the amino acid modifications that take place at the 2
l e v e l of amino acyl-tRNA ( e . g . the formation of N-formyl Met -tRNA) should presumably be r e f e r r e d to as p r e t r a n s l a t i o n a l modi fications. There is probably some merit in this system from the p o i n t of view of economy of communication, but i t i s a l s o probably safe to say that at the current s t a t e of knowledge the assignment of a given m o d i f i c a t i o n r e a c t i o n to p r e - , co- or p o s t t r a n s l a t i o n a l status w i l l be mostly s p e c u l a t i v e , and i n t h i s paper the s i n g l e d e s i g n a t i o n p o s t t r a n s l a t i o n a l w i l l be used f o r a l l these r e a c tions. The b i o l o g i c a l f u n c t i o n of many of these p o s t t r a n s l a t i o n a l m o d i f i c a t i o n r e a c t i o n s i s a l s o tenuous at t h i s stage, even i f we can r a t i o n a l i z e some of them as components of w e l l understood processes. The most obvious example of such e s t a b l i s h e d p r o cesses i s the o x i d a t i o n of s u l f h y d r y l groups r e s u l t i n g i n the formation of d i s u l f i d e bridges which are e s s e n t i a l s t r u c t u r a l 0-8412-0543-4/80/47-123-049$05.00/0 © 1980 American C h e m i c a l Society Whitaker and Fujimaki; Chemical Deterioration of Proteins ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
Downloaded by FUDAN UNIV on March 7, 2017 | http://pubs.acs.org Publication Date: May 28, 1980 | doi: 10.1021/bk-1980-0123.ch002
50
C H E M I C A L DETERIORATION OF PROTEINS
features of most e x t r a c e l l u l a r n a t i v e p r o t e i n s . S i m i l a r l y , i n the case of r i g i d p r o t e i n s such as c o l l a g e n and e l a s t i n f i b e r s , s e v e r a l chemical r e a c t i o n s c o n s i s t i n g of h y d r o x y l a t i o n , oxida t i o n , and deamination occur. These subsequently lead to the c h a r a c t e r i s t i c covalent c r o s s l i n k i n g which provides the molecular b a s i s f o r the s t r u c t u r a l and e l a s t i c p r o p e r t i e s of connective t i s s u e s (_1). I t has a l s o been e s t a b l i s h e d that peroxidasecatalyzed halogenation of t h y r o g l o b u l i n i s an e s s e n t i a l step i n the b i o s y n t h e s i s of thyroxine, and that s e v e r a l of the r e v e r s i b l e m o d i f i c a t i o n steps (e.g. phosphorylation) are involved i n the r e g u l a t i o n of metabolic r e a c t i o n s through the a c t i v a t i o n or i n a c t i v a t i o n of enzymes and r e g u l a t o r y p r o t e i n s ( h i s t o n e s ) . Finally, recent s t u d i e s i n the area of g l y c o p r o t e i n s t r u c t u r e and f u n c t i o n suggest an important r o l e of the g l y c o s y l a t i o n r e a c t i o n s i n b i o l o g i c a l communications. Even when the purpose of a given p o s t t r a n s l a t i o n a l m o d i f i c a t i o n i s understood, an examination of how and where i t occurs i s a l s o l i k e l y to y i e l d only l i m i t e d information. The c e l l b i o l o g i c a l s i t e s and processes involved i n the r e a c t i o n s , the s p e c i f i c i t y by which c e r t a i n amino a c i d residues or s p e c i f i c peptide bonds are s e l e c t e d f o r chemical m o d i f i c a t i o n and the mechanism by which the transformations are c a r r i e d out remain obscure f o r a l a r g e number of these r e a c t i o n s . The f i e l d of p o s t t r a n s l a t i o n a l m o d i f i c a t i o n of p r o t e i n s has been reviewed (2, 3), and the main purpose of t h i s a r t i c l e i s to b r i n g e a r l i e r reviews up to date, and to explore some of the most recent developments i n the f i e l d . Figure 1 summarizes our current knowledge of p o s t t r a n s l a t i o n m o d i f i c a t i o n r e a c t i o n s . Since the d e t a i l e d l i s t i n g of most of these r e a c t i o n s has been reported before, the reader i s r e f e r r e d to the o r i g i n a l t a b u l a t i o n f o r proper nomenclature and l i t e r a t u r e r e f e r e n c e s . I f one considers a l l known covalent a l t e r a t i o n s of the polyamino a c i d chains produced by l i v i n g c e l l s , the t o t a l number and types of r e a c t i o n become r a t h e r unwieldy, and i t i s u s e f u l to c l a s s i f y them i n t o three broad groups: 1) m o d i f i c a t i o n (cleavage and formation) of the peptide bond, 2) m o d i f i c a t i o n of the terminal a-NU2 and α-COOH groups and 3) m o d i f i c a t i o n of amino a c i d s i d e chains. The f i r s t of these three w i l l not be con s i d e r e d i n t h i s d i s c u s s i o n beyond the reminder that l i m i t e d p r o t e o l y s i s i s an e s s e n t i a l and very broadly observed phenomenon i n a l l l i v i n g systems. Ever s i n c e i t was r e a l i z e d that, although the i n i t i a t i o n of p r o t e i n synthesis r e q u i r e s N-formylmethionine as the N-terminal residue the f i n i s h e d product i s r a r e l y , i f ever, found with that residue s t i l l attached, i t was c l e a r that most, perhaps even a l l , b i o l o g i c a l l y a c t i v e p r o t e i n s have undergone p r o t e o l y t i c cleavage. The recent s i g n a l peptide hypothesis has added another dimension to t h i s processing step i n proposing that a hydrophobic N-terminal sequence demonstrated f o r a l a r g e number of p r o t e i n precursors i s e s s e n t i a l i n d i r e c t i n g a given p r o t e i n to or through the membranes of the c e l l . This s i g n a l peptide i s
Whitaker and Fujimaki; Chemical Deterioration of Proteins ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
Whitaker and Fujimaki; Chemical Deterioration of Proteins ACS Symposium Series; American Chemical Society: Washington, DC, 1980.
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