"Long before it's in the papers"
June 11, 2012

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Watching tiny living machines self-assemble

June 11, 2012
Courtesy of Université de Montréal
and World Science staff

Sci­en­tists have de­vised a new way to see how pro­teins, ti­ny ma­chines nat­u­rally built in­side our bod­ies, as­sem­ble.

The re­search could help fight dis­eases such as Alzheimer’s and Parkin­son’s—caused by er­rors in as­sem­bly—or en­a­ble bio­engi­neers to make new mo­lec­u­lar ma­chines, the re­search­ers say. The study was pub­lished June 10 in the jour­nal Na­ture Struc­tur­al and Mo­lec­u­lar Bi­ol­o­gy.

Two dif­fer­ent as­sem­bly stages, shown as pur­ple and red, of the pro­tein ubiq­ui­tin and the flu­o­res­cent probe used to vis­u­al­ize these stage (tryp­to­phan, in yel­low). (Cred­it: Pe­ter Al­len)

“All crea­tures, from bac­te­ria to hu­mans, mon­i­tor and trans­form their en­vi­ron­ments us­ing small pro­tein nano­ma­chines made of thou­sands of atoms,” ex­plained the sen­ior au­thor of the stu­dy, Ste­phen Mich­nick of the Uni­vers­ity of Mont­real de­part­ment of bio­chem­is­try. 

“For ex­am­ple, in our si­nus­es, there are com­plex re­cep­tor pro­teins that are ac­ti­vat­ed in the pres­ence of dif­fer­ent odor molecules. Some of those scents warn us of dan­ger; oth­ers tell us that food is near­by.” 

Pro­teins are made of long chains of ami­no acids, which have evolved over mil­lions of years to self-as­sem­ble ex­tremely rapid­ly—often in thou­sandths of a sec­ond or less—in­to a work­ing “nano­ma­chine,” or mo­lec­u­lar-scale ma­chine. “One of the main chal­lenges for bio­chemists is to un­der­stand how these lin­ear chains as­sem­ble in­to their cor­rect struc­ture giv­en an as­tro­nom­ic­ally large num­ber of oth­er pos­si­ble forms,” Mich­nick said.

“To un­der­stand how a pro­tein goes from a lin­ear chain to a un­ique as­sem­bled struc­ture, we need to cap­ture snap­shots of its shape at each stage of as­sem­bly,” said Alex­is Vallée-Bélisle, a co-au­thor of the stu­dy. “The prob­lem is that each step ex­ists for a fleet­ingly short time and no avail­a­ble tech­nique en­a­bles us to ob­tain pre­cise struc­tur­al in­forma­t­ion on these states with­in such a small time frame. We de­vel­oped a strat­e­gy to mon­i­tor pro­tein as­sembly by in­te­grat­ing flu­o­res­cent probes through­out the lin­ear pro­tein chain so that we could de­tect the struc­ture of each stage of pro­tein as­sembly, step by step to its fi­nal struc­ture.”

The as­sembly pro­cess, which be­gins us­ing in­struc­tions in our DNA, is it­self not the end of its jour­ney. A pro­tein can change, through chem­i­cal modifica­t­ions or with age, to take on dif­fer­ent forms and func­tions. “Under­standing how a pro­tein goes from be­ing one thing to be­com­ing anoth­er is the first step to­wards un­der­standing and de­sign­ing pro­tein nanoma­chines for biotech­nolo­gies such as med­i­cal and en­vi­ron­men­tal di­ag­nos­tic sen­sors, drug syn­the­sis or de­liv­ery,” Vallée-Bélisle said.

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Scientists have developed a new approach to see how proteins, tiny machines naturally built inside our bodies, assemble. The research could help fight diseases such as Alzheimer’s and Parkinson’s—caused by errors in assembly—or enable bioengineers to make new molecular machines, the researchers say. The study was published June 10 in the journal Nature Structural and Molecular Biology. “In order to survive, all creatures, from bacteria to humans, monitor and transform their environments using small protein nanomachines made of thousands of atoms,” explained the senior author of the study, Stephen Michnick of the University of Montreal department of biochemistry. “For example, in our sinuses, there are complex receptor proteins that are activated in the presence of different odor molecules. Some of those scents warn us of danger; others tell us that food is nearby.” Proteins are made of long chains of amino acids, which have evolved over millions of years to self-assemble extremely rapidly—often in thousandths of a second or less—into a working “nanomachine,” or molecular-scale machine. “One of the main challenges for biochemists is to understand how these linear chains assemble into their correct structure given an astronomically large number of other possible forms,” Michnick said. “To understand how a protein goes from a linear chain to a unique assembled structure, we need to capture snapshots of its shape at each stage of assembly,” said Alexis Vallée-Bélisle, a co-author of the study. “The problem is that each step exists for a fleetingly short time and no available technique enables us to obtain precise structural information on these states within such a small time frame. We developed a strategy to monitor protein assembly by integrating fluorescent probes throughout the linear protein chain so that we could detect the structure of each stage of protein assembly, step by step to its final structure.” The assembly process, which begins using instructions in our DNA, is itself not the end of its journey. A protein can change, through chemical modifications or with age, to take on different forms and functions. “Understanding how a protein goes from being one thing to becoming another is the first step towards understanding and designing protein nanomachines for biotechnologies such as medical and environmental diagnostic sensors, drug synthesis of delivery,” Vallée-Bélisle said.